Feeling too hot or cold after breast cancer: is it just a nuisance or a potentially important prognostic factor?

Abstract

There is widespread recognition among both patients and caregivers that breast cancer patients often experience debilitating deficiencies in their ability to achieve thermal comfort, feeling excessively hot or cold under circumstances when others are comfortable. However, this symptom receives little clinical or scientific attention beyond identification and testing of drugs that minimise menopausal-like symptoms. Could some of these symptoms represent an important prognostic signal? Could thermal discomfort be among other cytokine-driven sickness behaviour symptoms seen in many breast cancer patients? While the literature reveals a strong link between treatment for breast cancer and some menopausal vasomotor symptoms (e.g. hot flashes also known as "hot flushes"), there is little data on quantitative assessment of severity of different types of symptoms and their possible prognostic potential. However, recent, intriguing studies indicating a correlation between the presence of hot flashes and reduced development of breast cancer recurrence strongly suggests that more study on this topic is needed. In comparison to reports on the phenomenon of breast cancer-associated hot flashes, there is essentially no scientific study on the large number of women who report feeling excessively cold after breast cancer treatment. Since similar acquired thermal discomfort symptoms can occur in patients with cancers other than breast cancer, there may be as yet unidentified cancer- or treatment-driven factor related to temperature dysregulation. In general, there is surprisingly little information on the physiological relationship between body temperature regulation, vasomotor symptoms, and cancer growth and progression. The goal of this article is twofold: (1) to review the scientific literature regarding acquired deficits in thermoregulation among breast cancer survivors and (2) to propose some speculative ideas regarding the possible basis for thermal discomfort among some of these women. Specifically, we suggest a potential association with excessive pro-inflammatory cytokine activity, similar to other cytokine-driven symptoms experienced after breast cancer, including fatigue and depression. We highlight the similarity of some breast cancer-associated thermal discomfort symptoms to those which occur during fever, suggesting the possibility that there may be common underlying changes in pro-inflammatory cytokine activity in both conditions. We anticipate that this contribution will stimulate additional scientific interest among researchers in identifying potential mechanisms and prognostic significance of this under-studied aspect of breast cancer biology and survivorship.

Figure 1

Quantification of scientific literature pertaining to “feeling cold and cancer” reveals far fewer references than those studying “hot flashes and cances”. Moreover, literature involving hot flashes and cancer has been steadily increasing in numbers over the past decade while articles pertaining to feeling cold remain infrequent.

Figure 2

Humans must balance the amount of energy they consume, in the form of food, with the amount of energy they expend, through basal metabolism (homeothermy and biological maintenance), thermogenesis, and physical activity. When excess energy is required for one process utilizing energy, less energy is available to sustain other processes.

Figure 3

Summary of therapeutic and physiological influences on the thermoregulatory pathway and hot flashes. Generally, menopause reduces estrogen and progesterone levels. See text for additional details. SSRIs: selective serotonin reuptake inhibitors; SNRIs: serotonin-norepinephrine reuptake inhibits; SERMs: selective estrogen replacement moudulators; AIs Aromatase Inhibitors; MPA: medroxyprogesterone acetate.

Figure 4

The same cytokines are responsible for metabolic factors leading to cancer growth, fatigue, and temperature dysregulation (fever). High levels of TNF-α and IL-6 affect blood concentration and makeup leading to fatigue (blue). Increases in TNF-α and IL-6 promote metabolic syndrome (green) which induces gluconeogenesis and adipocyte production. These bodily changes lead to an upregulation of various immune regulators that result in cancer development and growth. These cytokines also lead to fever via a PGE-2 dependent pathway (red). Temperature dysregulation (feeling cold) has been related to fatigue and may also be associated with cancer growth. RBC: red blood cell; COX-2: inducible cyclo-oxygenase, PGE2: prostaglandin E2; IGF-1: insulin-like growth factor 1; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: reactive oxygen species; DNA: deoxyribonucleic acid; VEGF: vascular endothelial growth factor