Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer

Hanyuda, Akiko; Kim, Sun A.; Martinez-Fernandez, A.; Qian, Zhi Rong; Yamauchi, Mai; Nishihara, Reiko; Morikawa, Teppei; Liao, Xiaoyun; Inamura, Kentaro; Mima, Kosuke; Cao, Yin; Zhang, Xuehong; Wu, Kana; Chan, Andrew T.; Giovannucci, Edward; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Shivdasani, Ramesh A.; Ogino, Shuji

doi:10.1245/s10434-015-4967-4

Cited by 31 publications

(37 citation statements)

References 73 publications

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“…Four reports (38)(39)(40)(41) described participants from the Nurses' Health Study and Health Professionals Follow-up Health Study with respect to postdiagnosis physical activity and colorectal cancer-specific mortality, stratified by molecular subtype. Meyerhardt and colleagues (39) explored six molecular targets; Morikawa and colleagues (40) analyzed nuclear CTNNB1 status;…”

Section: Associations In Molecular Subgroupsmentioning

confidence: 99%

Physical Activity and Cancer Outcomes: A Precision Medicine Approach

Friedenreich

Neilson

Farris

et al. 2016

Clinical Cancer Research

257

168

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There is increasing interest in applying a precision medicine approach to understanding exercise as a potential treatment for cancer. We aimed to inform this new approach by appraising epidemiologic literature relating postdiagnosis physical activity to cancer outcomes overall and by molecular/genetic subgroups. Across 26 studies of breast, colorectal, and prostate cancer patients, a 37% reduction was seen in risk of cancer-specific mortality, comparing the most versus the least active patients (pooled relative risk = 0.63; 95% confidence interval: 0.54-0.73). Risks of recurrence or recurrence/cancer-specific death (combined outcome) were also reduced based on fewer studies. We identified ten studies of associations between physical activity and cancer outcomes by molecular or genetic markers. Two studies showed statistically significant risk reductions in breast cancer mortality/recurrence for the most (versus least) physically active estrogen receptor-positive/progesterone receptor-positive (ER/PR) patients, while others showed risk reductions among ERPR and triple-negative patients. In colorectal cancer, four studies showed statistically significant risk reductions in cancer-specific mortality for patients with high (versus low) physical activity and P21 expression, P27 expression, nuclear CTNNB1, PTGS2 (COX-2), or IRS1 low/negative status. One prostate cancer study showed effect modification by Gleason score. As a means to enhance this evidence, future observational studies are needed that will measure physical activity objectively before and after diagnosis, use standardized definitions for outcomes, control for competing risks, assess nonlinear dose-response relations, and consider reverse causality. Ultimately, randomized controlled trials with clinical cancer outcomes and a correlative component will provide the best evidence of causality, relating exercise to cancer outcomes, overall and for molecular and genetic subgroups. Clin Cancer Res; 22(19); 4766-75. ©2016 AACR.

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Section: Associations In Molecular Subgroupsmentioning

confidence: 99%

Physical Activity and Cancer Outcomes: A Precision Medicine Approach

Friedenreich

Neilson

Farris

et al. 2016

Clinical Cancer Research

257

168

View full text Add to dashboard Cite

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“…We confirmed reasonable agreements between the two pathologists, with j coefficients of 0.69, 0.77, 0.57, and 0.80, for IRS1, IRS2, FASN and CTNNB1, respectively, at p < 0.001. [29][30][31][32]…”

Section: Immunohistochemistrymentioning

confidence: 99%

Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers

Keum

Yuan

Nishihara

et al. 2017

Intl Journal of Cancer

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Accumulating evidence suggests that post-diagnostic insulin levels may influence colorectal cancer (CRC) survival. Yet, no previous study has examined CRC survival in relation to a post-diagnostic diet rich in foods that increase post-prandial insulin levels. We hypothesized that glycemic and insulin scores (index or load; derived from food frequency questionnaire data) may be associated with survival from specific CRC subtypes sensitive to the insulin signaling pathway. We prospectively followed 1,160 CRC patients from the Nurses’ Health Study (1980–2012) and Health Professionals Follow-Up Study (1986–2012), resulting in 266 CRC deaths in 10,235 person-years. CRC subtypes were defined by seven tumor biomarkers (KRAS, BRAF, PIK3CA mutations, and IRS1, IRS2, FASN, and CTNNB1 expression) implicated in the insulin signaling pathway. For overall CRC and each subtype, hazard ratio (HR) and 95% confidence interval (95% CI) for an increase of one standard deviation in each of glycemic and insulin scores were estimated using time-dependent Cox proportional hazards model. We found that insulin scores, but not glycemic scores, were positively associated with CRC mortality (HR=1.19, 95% CI=1.02 to 1.38 for index; HR=1.23, 95% CI=1.04 to 1.47 for load). The significant positive associations appeared more pronounced among PIK3CA wild-type cases and FASN-negative cases, with HR ranging from 1.36 to 1.60 across insulin scores. However, we did not observe statistically significant interactions of insulin scores with PIK3CA, FASN, or any other tumor marker (P interaction > .12). While additional studies are needed for definitive evidence, a high-insulinogenic diet after CRC diagnosis may contribute to worse CRC survival.

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“…Observational studies in CRC patients from two prospective cohorts (Nurses' Health Study [NHS] and Health Professionals Follow-Up Study [HPFS]) have investigated the interactions of tumor molecular alterations ( KRAS , PIK3CA , BRAF , CpG island methylator phenotype, and microsatellite instability) and protein expression patterns (fatty acid synthase, p53, p21, CDKN1B [p27], CTNNB1 [β-catenin], PTGS2 [COX-2], and insulin receptor substrate 1 [IRS1]) with post-diagnosis PA and its association with patient outcomes (54-57). The results of these studies suggest that p27, β-catenin, COX-2, and IRS1 expression significantly modifies the association of post-diagnosis PA with CRC-specific survival.…”

Section: Physical Activitymentioning

confidence: 99%

Vitamin D and Physical Activity in Patients With Colorectal Cancer

Morales-Oyarvide

Meyerhardt

2016

The Cancer Journal

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Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the U.S. Notwithstanding major improvements in the early detection and treatment of CRC, an important proportion of patients diagnosed with localized disease ultimately recur and die, underscoring the need of new therapeutic approaches. Vitamin D and physical activity (PA) have emerged as two potential interventions for both prevention and treatment of CRC. Plausible biological mechanisms have been described for the anti-neoplastic effects of vitamin D and PA, and a wealth of epidemiological evidence indicates that 25(OH)D (the main circulating form of vitamin D) and PA levels are inversely associated with CRC risk. Recent efforts have now focused on the role of vitamin D and PA as adjunct treatments after a CRC diagnosis. Observational studies evaluating pre- and post-diagnosis circulating 25(OH)D levels among patients with CRC of all stages have found that subjects with levels in the highest quantiles have improved overall and CRC-specific survival compared with those with levels in the lowest quantiles. Similarly, prospective studies of PA have found that higher levels of post-diagnosis PA are associated with lower overall and CRC-specific mortality in patients with non-metastatic CRC. Meta-analyses of the observational studies of 25(OH)D and post-diagnosis PA have confirmed significant protective associations against overall and CRC-specific mortality as well as significant dose-response relationships. No randomized, controlled trial of vitamin D or PA using survival outcomes as endpoints has been completed to date. Two randomized, placebo-controlled trials of vitamin D in patients with metastatic CRC assessing patient survival as an endpoint are underway: the first is a phase II trial comparing high-dose vitamin D3 (8000 IU day-1 for two weeks followed by 4000 IU day-1) versus standard dose (400 IU day-1), and the second is a phase I-II trial comparing customized oral doses of vitamin D3 titrated to raise serum 25(OH)D levels to 80-100 ng mL-1, versus 2000 IU day-1. For PA, the ongoing phase III Colon Health and Life-Long Exercise Change (CHALLENGE) study is the first randomized, controlled trial using survival as an endpoint among patients with stage II-III colon cancer. The results of these trials will pave the way to more conclusive phase III trials that will provide more definitive answers about the role of these interventions in the treatment of CRC. Lastly, the advent of genomic technologies will allow identifying molecular signatures in CRC associated with improved response to vitamin D and PA and will usher in a precision medicine approach to these therapies.

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Survival Benefit of Exercise Differs by Tumor IRS1 Expression Status in Colorectal Cancer

Cited by 31 publications

References 73 publications

Physical Activity and Cancer Outcomes: A Precision Medicine Approach

Physical Activity and Cancer Outcomes: A Precision Medicine Approach

Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers

Vitamin D and Physical Activity in Patients With Colorectal Cancer

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