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Review
. 2020 Apr 2:10:422.
doi: 10.3389/fonc.2020.00422. eCollection 2020.

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

Marco Invernizzi  1 , Gianluca Lopez  2   3 , Anna Michelotti  3 , Konstantinos Venetis  4   5 , Elham Sajjadi  3 , Leticia De Mattos-Arruda  6 , Michele Ghidini  7 , Letterio Runza  3 , Alessandro de Sire  1   8 , Renzo Boldorini  9 , Nicola Fusco  5   10
Affiliations
Review

Integrating Biological Advances Into the Clinical Management of Breast Cancer Related Lymphedema

Marco Invernizzi et al. Front Oncol. .

Abstract

Breast cancer-related lymphedema (BCRL) occurs in a significant number of breast cancer survivors as a consequence of the axillary lymphatics' impairment after therapy (mainly axillary surgery and irradiation). Despite the recent achievements in the clinical management of these patients, BCRL is often diagnosed at its occurrence. In most cases, it remains a progressive and irreversible condition, with dramatic consequences in terms of quality of life and on sanitary costs. There are still no validated pre-surgical strategies to identify individuals that harbor an increased risk of BCRL. However, clinical, therapeutic, and tumor-specific traits are recurrent in these patients. Over the past few years, many studies have unraveled the complexity of the molecular and transcriptional events leading to the lymphatic system ontogenesis. Additionally, molecular insights are coming from the study of the germline alterations involved at variable levels in BCRL models. Regrettably, there is a substantial lack of predictive biomarkers for BCRL, given that our knowledge of its molecular milieu remains extremely puzzled. The purposes of this review were (i) to outline the biology underpinning the ontogenesis of the lymphatic system; (ii) to assess the current state of knowledge of the molecular alterations that can be involved in BCRL pathogenesis and progression; (iii) to discuss the present and short-term future perspectives in biomarker-based patients' risk stratification; and (iv) to provide practical information that can be employed to improve the quality of life of these patients.

Keywords: breast cancer; breast cancer related lymphedema; genetics; pathobiology; quality of life; survivorship.

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Figures

Figure 1
Figure 1
Key molecular and transcriptional events in the lymphatic system ontogenesis. Different stages of lymphatic system development are outlined by their distinct stage-specific expression of different molecules. LEC, lymphatic endothelial cell.
Figure 2
Figure 2
Schematic representation of the fluid homeostasis based on the Starling equation. When the blood flow goes into the capillary, the capillary hydrostatic pressure (Pc) and the interstitial oncotic pressure (πi) drive oxygen and nutrients toward body's cells. Conversely, when blood moves toward venules, the interstitial fluid hydrostatic pressure (Pi) along with the plasma oncotic pressure (πp), which are mainly applied by the surrounding proteins, drive wastes and carbon dioxide into the capillary and subsequently out of the body.
Figure 3
Figure 3
Representative structure of the different types of lymphatic vessels. Small, branching lymphatic capillaries lined by a single file of lymphatic endothelial cells (LEC) are connected to pre-collector lymphatic vessels, showing tracts with a discontinuous basal lamina. The collecting vessels, whose functional unit is the lymphangion, are larger in diameter and have a prevalent propulsion function.
Figure 4
Figure 4
Oncoprint visualization of the somatic molecular alterations in breast cancers (n = 3,394 samples) involving 22 genes with reported germline alterations in BCRL patients. Each column represents a sample, each row represents a gene, as reported on the left. The genes were sorted by alterations frequency (percentage on the left). Types of alterations and study of origin (publicly available at cBioportal.com) are color-coded on the basis of the legend on the bottom.
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