Based on our findings, we considered whether PM loss may be correlated with progressive bone metastasis. The continuous decline in PM in light of increasing and fluctuating TU best matches the course of cachexia as it is currently understood as a metabolic phenomenon that is irreversible, unlike anorexia. Waning and Guise suggested that tumor growth in bone induces the release of bone-derived growth factors that may then act systematically to reduce muscle mass, reduce muscle function, and cause muscle weakness.4 Together, these results suggest an association of metastatic disease tumor burden with muscle loss. In addressing the high correlation of weight versus SF, one must consider that fat in the body fluctuates more rapidly in response to external factors than muscle content and can therefore contribute more dramatically to weight. In contrast, muscle loss may be less directly correlated with muscle mass due to differences in proximity to sites of bone metastases, yet related to the extent of boney metastasis.5 The AM parameters were seen to correlate strongly with weight, which could be an artifact of fat correlation with weight. Myosteatosis was radiologically evident in the AM, and therefore, an increase in weight that could be due to an increase in fat content may appear to be correlated with the corresponding rise in the AM width. Meanwhile, the continuous decline in PM could describe an underlying relationship between muscle mass and the adjacent site of bony metastatic bone disease.
In breast cancer, bone is the most common site of metastasis. Osteolytic boney lesions arise due to an imbalance in osteoclast-versus-osteoblast activity and are associated with cause pain, increased risk of fracture, and muscle weakness and fatigue.12 This fatigue and muscle weakness, associated with cancer cachexia, may be due to the coupled nature of muscle and bone anabolism/catabolism effects, due to paracrine and endocrine signals between muscle cells and bone factors.12 One such signaling molecule transforming growth factor beta (TGF-β), a potent regulator of wound healing in muscle, has been shown to impair myocyte differentiation and is overexpressed with osteolytic lesions. Similarly, calcitriol, a well-known bone differentiation signaling factor that is downregulated in osteolysis secondary to hypercalcemia, could influence muscle function.12 Yet another mediator, parathyroid hormone-related protein (PTHrP), released in breast cancer, may aid in its metastasis to the bone by promoting osteolysis that induces release of TGF-β.4 Therefore, PTHrP may have a direct effect on muscle function and mass by inducing osteolysis4 and by inducing uncoupling of electron transport from mitochondrial membranes to cause a negative energy balance.4,6,22 Therefore, with PTHrP being a common paraneoplastic syndrome of breast cancer, this may suggest an important mechanism for breast cancer-associated cachexia, representing a higher potential for cachexia to arise in cases of breast cancer than previously assumed.
Given the influential role of cachexia in the clinical presentation of our breast cancer patients, yet low documentation thereof, it is important to overcome the problem of its underdiagnosis in clinical practice. Early diagnosis of cachexia via careful monitoring of muscle wasting, perhaps through routine radiological studies, could allow for earlier intervention and therefore prevention of energy deprivation. Furthermore, recognizing the interrelationship between muscle wasting and tumor metastasis to the skeletal system as an important mechanism behind the rise of cachexia in breast cancer, is a step toward building new methods for early diagnosis of metastasis. In a review of the Waning et al study, Guttridge5 pointed out that it would be beneficial to build cohorts to study the levels of possible cachectic molecular factors in multiple types of cancer patients with bone metastases, one example of how studies of cachectic factors in cancer patients with bone metastases could be planned in the future. Moreover, distinguishing the muscle group most closely associated with tumor metastasis to the bone could provide for an improved method of detecting metastasis with high sensitivity and high specificity.
Given that this is a reported case, further studies with a larger cohort of patients could further reveal whether the correlations we have delineated between PM and TU in a single-case study persist across the subpopulation of breast cancer patients. In such studies, important physiological comorbidities that could be confounders for cachexia, including kidney disease, heart disease, chronic obstructive pulmonary disease, and age-related sarcopenia, could be evaluated against metastatic breast cancer as inducers of atrophy in PM. Additionally, a comparison could be made between changes in PM mass and other muscle mass changes to test for specificity. The pathological extent and burden of metastases in all cancer patients considered need to be evaluated against the value of PM loss in breast cancer patients with metastases to other organs. With further understanding of the relationship between muscle mass and physiological versus pathological extent of metastatic disease, monitoring muscle mass changes with imaging studies could allow for earlier detection of new metastatic sites.
While cancer-related cachexia is commonly attributed to decreased appetite and chemotherapy side effects, it is rarely correlated directly with clinical events or interventions. Our patient’s advanced breast cancer was associated with severe cachexia, considered to be a rare combination in breast cancer. Based on our data and review of the literature in this case study, longitudinal monitoring of cachexia in selected muscle groups can give clinicians early indications of the extent of cachexia in metastatic cancer patients. Although limited in its scope, this study also raises the question whether monitoring of PM wasting may serve as a prognostic factor for both cachexia and metastatic extent of the associated cancer, especially in breast cancer.
We thank L. Schwartz (Columbia University) for sharing his insights in this study.
ACADEMIC EDITOR: William Chi-shing Cho, Editor in Chief
PEER REVIEW: Four peer reviewers contributed to the peer review report. Reviewers’ reports totaled 333 words, excluding any confidential comments to the academic editor.
FUNDING: SA is an assistant professor of Avon Products Foundation at Columbia University and a recipient of the Pathway to Independence K99/R00 award (CA172697) and METAvivor award. KK was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number KL2 TR000081. SA was supported by the start-up funds of Columbia University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal.
COMPETING INTERESTS: Authors disclose no potential conflicts of interest.
Paper subject to independent expert blind peer review. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE).
Conceived and designed the experiments: KK, SA. Performed case study patient chart review: NC. Analyzed the data: NC. Wrote the software used for imaging analysis: XG, BZ. Performed histology and pathology: CC, HH. Directed the statistical data analysis: SLP. Wrote the first draft of the manuscript: NC. Contributed to the writing of the manuscript: NC, XG, BZ, CC, SLP, HH, KK, SA. Agreed with manuscript results and conclusions: NC, KK, SA, XG, CC, SLP, HH, BZ. Jointly developed the structure and arguments for the paper: NC, KK, SA. Made critical revisions and approved the final version: NC, KK, SA. All authors read and approved the final manuscript.
1. Kovarik M, Hronek M, Zadak Z. Clinically relevant determinants of body composition, function and nutritional status as mortality predictors in lung cancer patients. Lung Cancer. 2014;84(1):1–6. [PubMed]
2. Evans WJ, Morley JE, Argiles J, et al. Cachexia: a new definition. Clin Nutr. 2008;27(6):793–9. [PubMed]
3. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89(2):381–410. [PubMed]
6. Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer. 2014;14(11):754–62. [PubMed]
8. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64. [PubMed]
10. Spano D, Heck C, De Antonellis P, Christofori G, Zollo M. Molecular networks that regulate cancer metastasis. Semin Cancer Biol. 2012;22(3):234–49. [PubMed]
11. Tisdale MJ. Cancer cachexia. Curr Opin Gastroenterol. 2010;26(2):146–151. [PubMed]
13. Fearon KC. Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur J Cancer. 2008;44(8):1124–32. [PubMed]
15. Zhao B, Colville J, Kalaigian J, et al. Automated quantification of body fat distribution on volumetric computed tomography. Journal of computer assisted tomography. 2006 Sep-Oct;30(5):777–83. [PubMed]
16. Blum D, Omlin A, Baracos VE, et al. Cancer cachexia: a systematic literature review of items and domains associated with involuntary weight loss in cancer. Critical reviews in oncology/hematology. 2011 Oct;80(1):114–44. [PubMed]
17. Martin L, Senesse P, Gioulbasanis I, et al. Diagnostic criteria for the classification of cancer-associated weight loss. Journal of clinical oncology:official journal of the American Society of Clinical Oncology. 2015 Jan 1;33(1):90–9. [PubMed]
18. Acerbo AS, Carr GL, Judex S, Miller LM. Imaging the material properties of bone specimens using reflection-based infrared microspectroscopy. Anal Chem. 2012;84(8):3607–13. [PMC free article] [PubMed]
21. Baracos VE, Reiman T, Mourtzakis M, Gioulbasanis I, Antoun S. Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J Clin Nutr. 2010;91(4):1133S–7S. [PubMed]
Source: Clinical Medicine Insights: Oncology.
Originally published September 11, 2016.