Sleep Apnea and Cancer

Obstructive sleep apnea promotes cancer development and progression: a concise review.

Cao J1, Feng J, Li L, Chen B. Sleep Breath. 2015 May;19(2):453-7

BACKGROUND: Obstructive sleep apnoea-hypopnoea (OSA) is an increasingly common sleep disorder which is widely accepted to be associated with high rates of morbidity and mortality. OSA is an independent risk factor for cardiovascular diseases, cerebrovascular disease, and metabolic disease. Recently, several studies have demonstrated that patients with OSA have a higher prevalence of cancer and cancer-related mortality. The epidemiological surveys suggest that patients with OSA had a higher incidence of cancer and cancer-related mortality than patients without OSA. Animal studies indicate that the activation of HIF-1 and VEGF pathways in response to intermittent hypoxia may promote the blood supply which supports tumor growth. In addition, tumor-associated macrophages may be altered by intermittent hypoxia (or sleep fragmentation) to a tumor-promoting phenotype yielding more aggressive cancer behaviour.

CONCLUSIONS: The relationship between OSA and cancer has been confirmed, in which patients with OSA have a relative high prevalence of cancer and cancer-related mortality. The mechanism of OSA promoting cancer development and progression may be related with intermittent hypoxia and possibly sleep fragmentation. The activation of several cancer-related pathways may play an important role in tumor growth and metastasis. More clinical data and basic studies are needed to explain and confirm the relationship between OSA and cancer.

Obstructive sleep apnea and cancer: effects of intermittent hypoxia?

Kukwa W1, Migacz E1, Druc K2, Grzesiuk E3, Czarnecka AM2. Future Oncol. 2015;11(24):3285-98.

Obstructive sleep apnea (OSA) is a common disorder characterized by pauses in regular breathing. Apneic episodes lead to recurrent hypoxemia-reoxygenation cycles with concomitant cellular intermittent hypoxia. Studies suggest that intermittent hypoxia in OSA may influence tumorigenesis. This review presents recent articles on the potential role of OSA in cancer development. Relevant research has focused on: molecular pathways mediating the influence of intermittent hypoxia on tumor physiology, animal and epidemiological human studies linking OSA and cancer. Current data relating OSA to risk of neoplastic disease remain scarce, but recent studies reveal the potential for a strong relation. More work is, therefore, needed on the impact of OSA on many cancer-related aspects. Results may offer enlightenment for improved cancer diagnosis and treatment.

Cancer and OSA: Current Evidence From Human Studies.

Martínez-García MÁ1, Campos-Rodriguez F2, Barbé F3. Chest. 2016 Aug;150(2):451-63.

Despite the undeniable medical advances achieved in recent decades, cancer remains one of the main causes of mortality. It is thus extremely important to make every effort to discover new risk factors for this disease, particularly ones that can be treated or modified. Various pathophysiologic pathways have been postulated as possible causes of cancer or its increased aggressiveness, and also of greater resistance to antitumoral treatment, in the presence of both intermittent hypoxia and sleep fragmentation (both inherent to sleep apnea).

Thus far, these biological hypotheses have been supported by various experimental studies in animals. Meanwhile, recent human studies drawing on preexisting databases have observed an increase in cancer incidence and mortality in patients with a greater severity of sleep-disordered breathing. However, the methodologic limitations of these studies (which are mostly retrospective and lack any measurement of direct markers of intermittent hypoxia or sleep fragmentation) highlight the need for controlled, prospective studies that would provide stronger scientific evidence regarding the existence of this association and its main characteristics, as well as explore its nature and origin in greater depth. The great epidemiologic impact of both cancer and sleep apnea and the potential for clinical treatment make this field of research an exciting challenge.

Sleep and Breathing… and Cancer?: A report from the University of California San Diego Sleep and Cancer Symposium, January 5- 6th, 2016 in La Jolla, CA.

Owens RL1, Gold K2, Gozal D3, Peppard PE4, Jun J5, Lippman SM6, Malhotra A7. Cancer Prev Res (Phila). 2016 Sep 7

Sleep, like eating and breathing, is an essential part of the daily life cycle. Although the science is still emerging, sleep plays an important role in immune, cardiovascular, and neurocognitive function. Despite its great importance, nearly 40% of US Adults experience problems with sleep ranging from insufficient total sleep time, trouble initiating or maintaining sleep (Insomnia), Circadian Rhythm Disorders, Sleep-Related Movement Disorders, and Sleep-Related Breathing Disorders such as obstructive sleep apnea (OSA). Herein, we discuss new evidence that suggests that sleep may also impact carcinogenesis. Specifically, we review recent epidemiological data suggesting links between cancer and OSA.

As OSA is a common, underdiagnosed, and undertreated condition, this has public health implications. Intriguing animal model data support a link between cancer and sleep/OSA, although mechanisms are not yet clear. Leaders in the fields of Sleep Medicine, Pulmonology and Oncology recently met to review and discuss these data, as well as to outline future directions of study. We propose a multidisciplinary, three-pronged approach to studying the associations between cancer and sleep, utilizing mutually interactive epidemiologic studies, pre-clinical models, and early-phase clinical trials.

Sleep-disordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study.

Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R. University of Wisconsin-Madison, Madison, WI, USA. Am J Respir Crit Care Med. 2012 Jul 15;186(2):190-4.

RATIONALE: Sleep-disordered breathing (SDB) has been associated with total and cardiovascular mortality, but an association with cancer mortality has not been studied. Results from in vitro and animal studies suggest that intermittent hypoxia promotes cancer tumor growth.

OBJECTIVES: The goal of the present study was to examine whether SDB is associated with cancer mortality in a community-based sample.

METHODS: We used 22-year mortality follow-up data from the Wisconsin Sleep Cohort sample (n = 1,522). SDB was assessed at baseline with full polysomnography. SDB was categorized using the apnea-hypopnea index (AHI) and the hypoxemia index (percent sleep time below 90% oxyhemoglobin saturation). The hazards of cancer mortality across levels of SDB severity were compared using crude and multivariate analyses.

MEASUREMENTS AND MAIN RESULTS: Adjusting for age, sex, body mass index, and smoking, SDB was associated with total and cancer mortality in a dose-response fashion. Compared with normal subjects, the adjusted relative hazards of cancer mortality were 1.1 (95% confidence interval [CI], 0.5-2.7) for mild SDB (AHI, 5-14.9), 2.0 (95% CI, 0.7-5.5) for moderate SDB (AHI, 15-29.9), and 4.8 (95% CI, 1.7-13.2) for severe SDB (AHI ≥ 30) (P-trend = 0.0052). For categories of increasing severity of the hypoxemia index, the corresponding relative hazards were 1.6 (95% CI, 0.6-4.4), 2.9 (95% CI, 0.9-9.8), and 8.6 (95% CI, 2.6-28.7).

CONCLUSIONS: Our study suggests that baseline SDB is associated with increased cancer mortality in a community-based sample. Future studies that replicate our findings and look at the association between sleep apnea and survival after cancer diagnosis are needed.

Tumor Cell Malignant Properties Are Enhanced by Circulating Exosomes in Sleep Apnea.

Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farré R. University of Wisconsin-Madison, Madison, WI, USA. Am J Respir Crit Care Med. 2012 Jul 15;186(2):190-4.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. Exosomes are vesicles secreted by most cells, are released into the bloodstream, and play a role in tumor progression and metastasis. Here, we evaluated whether the chronic intermittent hypoxia (IH) that characterizes OSA leads to release of tumor-promoting exosomes in circulation.

METHODS: C57/B6 male mice were randomized to 6 weeks of IH or room air (RA). A subgroup of the mice was injected with TC1 lung carcinoma cells in the left flank after 2 weeks of IH. Exosomes from mouse plasma and from 10 adult human patients with OSA before (Pre) and after adherent treatment for 6 wks (Post) were co-cultured with mouse TC1 and human adenocarcinoma cells lines. Malignant tumor properties such as proliferation, migration, invasion and endothelial monolayer disruption were assessed, as well as miRNA exosomal content and transcriptomic effects of exosomes on TC1 cells in vitro to identify target genes.

RESULTS: Application of IH-induced exosomes from either IH-exposed tumor bearing (IH (+) or non-bearing mice IH (-) significantly promoted TC1 malignant properties. Similarly, Pre exosomes from OSA patients significantly enhanced proliferation and migration of human adenocarcinoma cells compared to Post. 11 distinct miRNAs emerged in IH (-) mice and their gene targets in TC1 cells were identified.

CONCLUSION: Circulating exosomes released under IH conditions in vivo selectively enhance specific properties of lung tumor cell cultures. Thus, plasma exosomes participate in the increased tumor aggressiveness observed in OSA patients.

Obstructive sleep apnea is associated with an increased risk of colorectal neoplasia.

Lee S1, Kim BG1, Kim JW1, Lee KL1, Koo DL2, Nam HW2, Im JP3, Kim JS3, Koh SJ4. Gastrointest Endosc. 2016 Aug 6.

BACKGROUND AND AIMS: A recent meta-analysis showed that obstructive sleep apnea (OSA) is associated with a higher prevalence of cancer and cancer-related mortality; however, little information is available on the association between OSA and colorectal neoplasia.

METHODS: We identified consecutive patients who underwent overnight polysomnography (PSG) and subsequent colonoscopy. We compared the prevalence of colorectal neoplasia between patients with or without OSA according to the results of PSG. For each OSA case, 1 or 2 age-matched (± 5 years), sex-matched, body mass index (BMI), and smoking-matched controls who had undergone first-time screening colonoscopy were selected.

RESULTS: Of the 163 patients, 111 patients were diagnosed with OSA and 52 patients showed normal range of apnea-hypopnea index. Of the 111 patients with OSA, 18 patients (16.2%) had advanced colorectal neoplasia, including 4 (3.6%) colorectal cancers. In the multivariate analyses, OSA was associated with an increased risk of advanced colorectal neoplasia after adjusting for factors including age and sex (mild, odds ratio [OR], 14.09; 95% confidence interval [CI], 1.55-127.83; P = 0.019; moderate or severe, OR, 14.12; 95% CI, 1.52-131.25; P = 0.020). Our case-control study revealed that the odds of detecting advanced colorectal neoplasia among patients with OSA were approximately 3.03 times greater than in the age-, sex-, BMI-, and smoking-matched controls (OR, 3.03; 95% CI, 1.44-6.34; P = 0.002).

CONCLUSION: Physicians should be aware of the association between OSA and the development of colorectal neoplasia and explain the need for colonoscopy to patients with OSA.

Associations of self-reported sleep duration and snoring with colorectal cancer risk in men and women.

Zhang X, Giovannucci EL, Wu K, Gao X, Hu F, Ogino S, Schernhammer ES, Fuchs CS, Redline S, Willett WC, Ma J. Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. Sleep. 2013 May 1;36(5):681-8.

STUDY OBJECTIVES: We assessed the relationship between sleep duration, snoring and colorectal cancer risk. DESIGN: Prospective cohort studies.

SETTING: United States.

PARTICIPANTS: A total of 30,121 men aged 41 to 79 years in the Health Professionals Follow-up Study and 76,368 women aged 40 to 73 years in the Nurses’ Health Study.


MEASUREMENTS AND RESULTS: We queried information on sleep duration and snoring in 1986/87. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs, 95% CIs). We documented 1,973 incident colorectal cancer cases (709 men and 1,264 women) over a 22-year follow-up period. Compared to sleep an average 7 h, ≥ 9 h of sleep was significantly associated with a higher risk of colorectal cancer among men (HR = 1.35, 95% CI: 1.00, 1.82), and to a lesser degree, among women (HR = 1.11, 95% CI: 0.85, 1.44). The risk associated with longer sleep was restricted to individuals who regularly snored (men: HR = 1.80, 95% CI: 1.14, 2.84; women: HR = 2.32, 95% CI: 1.24, 4.36) and to overweight individuals (i.e., BMI ≥ 25 kg/m2) (men: HR = 1.52, 95% CI: 1.04, 2.21; women: HR = 1.37, 95% CI: 0.97, 1.94). Short sleep duration (≤ 5 h) was not associated with an increased risk of colorectal cancer in the entire sample or in subgroups stratified by snoring or BMI.

CONCLUSIONS: Longer sleep duration was associated with an increased risk of developing colorectal cancer among individuals who were overweight or snored regularly. This observation raises the possibility that sleep apnea and its attendant intermittent hypoxemia may contribute to cancer risk.

Sleep Apnea and Cancer: Analysis of a Nationwide Population Sample.

Gozal D1, Ham SA2, Mokhlesi B3. Sleep. 2016 Aug 1;39(8):1493-500

STUDY OBJECTIVES: Epidemiological evidence from relatively small cohorts suggests that obstructive sleep apnea (OSA) is associated with higher cancer incidence and mortality. Here we aimed to determine whether cancer incidence for major cancer types and risk of metastases or mortality from cancer are increased in the presence of OSA.

METHODS: All OSA diagnoses included in an employee-sponsored health insurance database spanning the years 2003-2012 were identified and 1:1 matched demographically based on age, gender, and state of residence, or alternatively matched by comorbidities. The incidence of 12 types of cancer was assessed. In addition, another cohort of patients with a primary diagnosis of cancer was retrieved, and the risk of metastatic disease or cancer mortality was determined as a function of the presence or absence of OSA. Multivariate Cox proportional hazards regression models were fitted to assess the independent associations between OSA and outcomes of interest.

RESULTS: Based on a cohort of ∼5.6 million individuals, the incidence of all cancer diagnoses combined was similar in OSA and retrospectively matched cases. However, the adjusted risk of pancreatic and kidney cancer and melanoma were significantly higher in patients with OSA, while the risk of colorectal, breast, and prostate cancers appeared to be lower. Among individuals with a diagnosis of cancer, the presence of OSA was not associated with an increased risk for metastasis or death.

CONCLUSIONS: In a large nationally representative health insurance database, OSA appears to increase the risk for only a very selective number of cancer types, and does not appear to be associated with an increased risk of metastatic cancer or cancer-related deaths.

Association between sleep-disordered breathing, obstructive sleep apnea, and cancer incidence: a systematic review and meta-analysis.

Palamaner Subash Shantha G1, Kumar AA2, Cheskin LJ3, Pancholy SB4. Sleep Med. 2015 Oct;16(10):1289-94.

OBJECTIVE/BACKGROUND: Via this systematic review and meta-analysis, we assessed the associatio between sleep-disordered breathing (SDB)/obstructive sleep apnea (OSA) and cancer incidence.

METHOD: Medline, Embase, Cochrane Central, and electronic databases were searched for relevant studies in any language. Studies were included based on the following criteria: (1) those on patients with SDB/OSA, (2) those reporting cancer incidence rates specific to patients with SDB/OSA, and (3) those defining SDB/OSA using sleep-study-based objective measures. The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOQA).

RESULTS: Of the 8766 retrieved citations, five studies that defined SDB/OSA using the apnea-hypopnea index (AHI) or the respiratory disturbance index (RDI) totaling 34,848 patients with SDB and 77,380 patients without SDB were pooled into a meta-analysis. All five studies were of good quality (NOQA ≥ 6). A total of 574 (1.6%) and 290 (0.37%) incident cancers were reported in patients with and without SDB, respectively. In the unadjusted analysis, patients with SDB/OSA were at an increased risk of incident cancer (relative risk [RR]: 1.53, 95% confidence interval [CI]: 1.31-1.79, P <0.001, I(2): 0, five included studies). When adjusted for traditional cancer risk factors, the association between SDB/OSA and cancer incidence, although attenuated (RR: 1.40, 95% CI: 1.01-1.95, P = 0.04, I(2): 60%, five included studies), remains significant.

CONCLUSIONS: SDB/OSA may increase the risk of incident cancer. Inferring an independent association is not possible from our analysis considering the retrospective cohort design of the included studies and high inter-study heterogeneity. An individual patient data meta-analysis would help validate our findings.

Obstructive sleep apnea is associated with cancer mortality in younger patients.

Martínez-García MA, Campos-Rodriguez F, Durán-Cantolla J, de la Peña M, Masdeu MJ, González M, Del Campo F, Serra PC, Valero-Sánchez I, Ferrer MJ, Marín JM, Barbé F, Martínez M, Farré R, Montserrat JM; Spanish Sleep Network. Sleep Med. 2014 Jul;15(7):742-8.

OBJECTIVE: The association between obstructive sleep apnea (OSA) and cancer mortality has scarcely been studied. The objective of this study was to investigate whether OSA is associated with increased cancer mortality in a large cohort of patients with OSA suspicion.

METHODS: This was a multicenter study in consecutive patients investigated for suspected OSA. OSA severity was measured by the apnea-hypopnea index (AHI) and the hypoxemia index (% night-time spent with oxygen saturation <90%, TSat90). The association between OSA severity and cancer mortality was assessed using Cox’s proportional regression analyses after adjusting for relevant confounders.

RESULTS: In all, 5427 patients with median follow-up of 4.5 years were included. Of these, 527 (9.7%) were diagnosed with cancer. Log-transformed TSat90 was independently associated with increased cancer mortality in the entire cohort (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.42), as well as in the group of patients with cancer (HR, 1.19; 95% CI, 1.02-1.41). The closest association was shown in patients <65years in both the AHI (continuous log-transformed AHI: HR, 1.87; 95% CI, 1.1-3.2; upper vs lower AHI tertile: HR, 3.98; 95% CI, 1.14-3.64) and the TSat90 (continuous log-transformed TSat90: HR, 1.73; 95% CI, 1.23-2.4; upper vs. lower TSat90 tertile: HR, 14.4; 95% CI, 1.85-111.6). CONCLUSIONS: OSA severity was associated with increased cancer mortality, particularly in patients aged <65 years.

Risk of Cancer in Patients with Insomnia, Parasomnia, and Obstructive Sleep Apnea: A Nationwide Nested Case-Control Study.

Fang HF1, Miao NF2, Chen CD3, Sithole T4, Chung MH5. J Cancer. 2015 Sep 15;6(11):1140-7.

PURPOSE: Insomnia, parasomnia, and obstructive sleep apnea have been associated with a number of disease pathologies, but little is known about the relationship of these sleep disorders and cancer. The study explored the risk of sleep disorder (SD)-induced cancer using nationwide population data. Two million data from the National Health Insurance system of Taiwan was used to assess for the relationship.

PATIENTS AND METHODS: Patients with cancer as our cases and patients without cancer as our control group in 2001-20011. The study patients were traced back to seek the exposure risk factor of sleep disorders, which was divided into three categories: insomnia, obstructive sleep apnea (OSA) and parasomnia. Patients were selected excluding patients who had cancer prior to presenting with the sleep disorder and the person-year is less than 2 years. Each case was randomly matched with two cases with the same age, gender, and index year.

RESULTS: There were significantly increased risks of breast cancer in the patients with insomnia (AHR=1.73; 95% CI: 1.57-1.90), patients with parasomnia (AHR=2.76; 95% CI: 1.53-5.00), and patients with OSA (AHR=2.10; 95% CI: 1.16-3.80). Moreover, patients with parasomnia had significantly higher risk of developing oral cancer (AHR=2.71; 95% CI: 1.02-7.24) compared with patients without parasomnia. The risk of suffering from nasal cancer (AHR=5.96, 95% CI: 2.96-11.99) and prostate cancer (AHR=3.69, 95% CI: 1.98- 6.89) in patients with OSA was significantly higher than that of patients without OSA.

CONCLUSIONS: Our findings provided the evidence that people diagnosed with insomnia, parasomnia and OSA are at a higher risk of developing cancers to remind people to improve sleep quality.

Sleep apnea and the subsequent risk of breast cancer in women: a nationwide population-based cohort study.

Chang WP, Liu ME, Chang WC, Yang AC, Ku YC, Pai JT, Lin YW, Tsai SJ. Yuanpei University, HsinChu, Taiwan. Sleep Med. 2014 Sep;15(9):1016-20.

BACKGROUND: Hypoxia plays an important role in the development of solid tumors. Intermittent hypoxia is the hallmark of sleep apnea (SA). We tested the hypothesis that SA may increase the risk of breast cancer in Taiwan by using a population-based data set.

METHODS: Our study cohort consisted of women diagnosed with SA between January 2003 and December 2005 (n = 846). For each SA patient, five age-matched control women were randomly selected as the comparison cohort (n = 4230). All participant cases were followed for 5 years from the index date to identify the development of breast cancer. Cox proportional-hazards regression was performed to evaluate the 5-year breast-cancer-free survival rates.

RESULTS: Forty-four women developed breast cancer during the 5-year follow-up period, among whom 12 were SA patients and 32 were in the comparison cohort. The adjusted hazard ratio (HR) of breast cancer in patients with SA was higher HR, 2.09; 95% confidence interval (CI), 1.06-4.12; P < 0.05] than that of the controls during the 5-year follow-up. Despite not meeting statistical significance, we found increases in the risk of breast cancer in women aged 30-59 years (HR, 2.06; 95% CI, 0.90-4.70) and ≥60 years (HR, 3.05; 95% CI, 0.90-10.32) compared with those aged 0-29 years.

CONCLUSION: The findings of our population-based study suggest an association between SA and an increased risk of breast cancer in women.

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