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DOI:10.32604/biocell.2022.021043		 images
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Biomarkers for targeted rehabilitation strategies after breast cancer: Proposal for the next-generation management of survivorship issues

MARCO INVERNIZZI1,2,* and NICOLA FUSCO3,4,*

1Translational Medicine, Dipartimento Attività Integrate Ricerca e Innovazione (DAIRI), Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, Alessandria, 15121, Italy
2Physical and Rehabilitation Medicine, Department of Health Sciences, University of Eastern Piedmont, Novara, 28100, Italy
3Division of Pathology, IEO, European Institute of Oncology IRCCS, Milan, 20141, Italy
4Department of Oncology and Hemato-Oncology, University of Milan, Milan, 20122, Italy
*Address correspondence to: Marco Invernizzi, marco.invernizzi@med.uniupo.it; Nicola Fusco, nicola.fusco@ieo.it
Received: 24 December 2021; Accepted: 14 February 2022

Keywords: Breast cancer; Biomarkers; Survivorship; Rehabilitation; Precision medicine

Breast cancer (BC) is the most common malignant tumor and one of the top causes of cancer-related death worldwide (Sung et al., 2021). The recent advances in early tumor diagnosis coupled with more effective treatment strategies resulted in a steady increase of long-term survivors (Nardin et al., 2020; Invernizzi et al., 2022). These improved survival rates led to a significantly higher incidence of disabling complications related to breast cancer and/or its treatment (Invernizzi et al., 2020a; D’Egidio et al., 2017; Zhong et al., 2020). These conditions have detrimental effects on patients’ health status, leading to a high burden of psychological suffering, functional impairment, and reduced health-related quality of life (HRQoL) (Sunilkumar et al., 2021). Not dissimilarly from the tumor, the diagnosis and treatment of survivorship issues require a precision medicine approach (Ballinger et al., 2021).

Only recently HRQoL became an integral part of the healthcare system and component of modern treatment strategies and translational studies design (Cheng et al., 2017). The ability to precisely assess and define HRQoL determines the success of oncological rehabilitation interventions in breast cancer (Rick et al., 2017). During the past few years, our research groups promoted a paradigm shift for the management of HRQoL issues in breast cancer survivors. This approach, both for translational research and clinical practice, is biomarker-based, akin to that for the management of the neoplasm itself (Pagni et al., 2019; Criscitiello et al., 2022; Pal et al., 2021; Fusco et al., 2021). In particular, we identified relevant subclasses of patients that could benefit from targeted rehabilitation strategies among the major HRQoL issues in breast cancer survivors. We focused our attention on breast cancer-related lymphedema (BCRL) (Invernizzi et al., 2018; Invernizzi et al., 2019; Michelotti et al., 2019; Invernizzi et al., 2020b; de Sire et al., 2021), axillary web syndrome (de Sire et al., 2020a), cancer treatment-induced bone loss (Venetis et al., 2021; Invernizzi et al., 2020c), aromatase inhibitor-induced arthralgia (Grizzi et al., 2020; de Sire et al., 2020b), and cancer related fatigue (Invernizzi et al., 2020d). More in detail, BCRL (i.e., localized retention of lymph, interstitial fluids, and proteins in the subcutaneous tissue of the upper limb after axillary dissection and/or radiation treatment) is an extremely disabling and progressive condition that affects ∼20% of breast cancer survivors (Gillespie et al., 2018). Recently, single nucleotide polymorphisms in ctDNA have been documented in BCRL patients, suggesting a possible role for individual predisposition in the development of BCRL (Hadizadeh et al., 2018; Smoot et al., 2017). These genes include lymphangiogenic and angiogenic genes (e.g., LCP2, NRP2, NFKB2), pro-inflammatory (e.g., IL1, IL2, IL8, IL17, NFKB2) and anti-inflammatory (e.g., IL4, IL10, IL13) cytokines, connexins, and potassium channel genes (e.g., KCNA1, KCNJ3, KCNJ6, KCNK3). Of note, specific biological characteristics of the primary tumors (e.g., laterality, lymph-vascular invasion, and extracapsular extension of the lymph node metastasis) can be employed as risk indicators (Invernizzi et al., 2018). Another major health issue in breast cancer survivors is persistent pain after the surgical procedure, which involves almost 30% of patients (Chang et al., 2021). In this condition, the inflammatory milieu is responsible for the peripheral sensitization and inflammatory pain hypersensitivity at inflamed sites, particularly nerves. The role of inflammasome and circulating biomarkers have also been explored in cancer related fatigue, one of the most burdensome and long-lasting side-effects of breast cancers (Vannorsdall et al., 2021). Despite circulating C-reactive protein and IL6 seem to be associated with an increased risk of CRF in long-term breast cancer survivors, these inflammatory markers are not yet ready to enter the clinical practice (Maurer et al., 2021).

The results of our studies provide strong evidence that under the umbrella of “quality of life interventions” stand a multitude of different conditions that are extremely heterogeneous in their biology, even in the presence of the same clinical manifestation. For this reason, individualized therapeutic approaches are required for the management of these conditions at a single-patient level. To achieve this goal, however, a multidisciplinary approach is required. We believe that the breast cancer healthcare community is ready for the “quantum leap” of implementing biomarkers for the clinical management of survivorship issues. Indeed, all these conditions are related not only to the active therapeutic oncological treatments but also to the tumor itself, which hinders cancer patients’ HRQoL. Thus, the concept of “quality of life interventions” should be expanded to the concept of Cancer Rehabilitation, which comprises a framework of distinct approaches, from different points of view, and by different specialists.

In conclusion, thanks to the increasing effectiveness of screening programs and treatment schemes, the number of women who die of breast cancer has gradually declined. In this scenario, the prolongation of patients’ life is no longer sufficient. Indeed, caregivers are now required to preserve and improve the HRQoL of patients. The next-generation model of “breast cancer survivorship” starts with the initial diagnosis and extends through the rest of the patient’s life according to patient-specific (and in some cases tumor-specific) biological characteristics (Duijts and Spelten, 2021; Chan et al., 2021). This complex and fascinating field requires dedicated translational research studies and clinical trials to be fully integrated into clinical practice.

Author Contribution: Both authors confirm sole responsibility for the following: study conception and design, manuscript preparation.

Funding Statement: The authors received no specific funding for this study.

Conflicts of Interest: M.I. has received honoraria for consulting, advisory role, and/or speaker bureau from SPA, Errekappa Euroterapici S.p.a. and Amgen. N.F. has received honoraria for consulting, advisory role, and/or speaker bureau from Merck Sharp & Dohme (MSD), Boehringer Ingelheim, Novartis, AstraZeneca, and Daiichi Sankyo. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results.

References

  1. Ballinger, TJ., Althouse, SK., Olsen, TP., Miller, KD., & Sledge, JS. (2021). A personalized, dynamic physical activity intervention is feasible and improves energetic capacity, energy expenditure, and quality of life in breast cancer survivors. Frontiers in Oncology, 11, 626180. [Google Scholar] [CrossRef]
  2. Chan, RJ., Nekhlyudov, L., Duijts, SFA., Hudson, SV., & Jones, JM. (2021). Future research in cancer survivorship. Journal of Cancer Survivorship, 15, 659-667. [Google Scholar] [CrossRef]
  3. Chang, PJ., Asher, A., & Smith, SR. (2021). A targeted approach to post-mastectomy pain and persistent pain following breast cancer treatment. Cancers, 13, 5191. [Google Scholar] [CrossRef]
  4. Cheng, KKF., Lim, YTE., Koh, ZM., & Tam, WWS. (2017). Home-based multidimensional survivorship programmes for breast cancer survivors. Cochrane Database of Systematic Reviews, 8, Cd011152. [Google Scholar] [CrossRef]
  5. Criscitiello, C., Guerini-Rocco, E., Viale, G., Fumagalli, C., & Sajjadi, E. (2022). Immunotherapy in breast cancer patients: A focus on the use of the currently available biomarkers in oncology. Anticancer Agents in Medinal Chemistry, 22, [Google Scholar] [CrossRef]
  6. de Sire, A., Fusco, N., Sajjadi, E., Lippi, L., Cisari, C., & Invernizzi, M. (2021). Lymphedema rehabilitation using self-adaptive inelastic compression in breast cancer: A proof-of-principle study. Applied Sciences, 11, 1901. [Google Scholar] [CrossRef]
  7. de Sire, A., Losco, L., Cisari, C., Gennari, A., Boldorini, R., Fusco, N., Cigna, E., & Invernizzi, M. (2020a). Axillary web syndrome in women after breast cancer surgery referred to an Oncological Rehabilitation Unit: Which are the main risk factors? A retrospective case-control study. European Review for Medical and Pharmacological Sciences, 24, 8028-8035. [Google Scholar]
  8. de Sire, A., Invernizzi, M., Lippi, L., Cisari, C., Özçakar, L., & Franchignoni, F. (2020b). Blurred lines between axillary web syndrome and Mondor’s disease after breast cancer surgery: A case report. Annals of Physical and Rehabilitation Medicine, 63, 365-367. [Google Scholar]
  9. D’Egidio, V., Sestili, C., Mancino, M., Sciarra, I., & Cocchiara, R. (2017). Counseling interventions delivered in women with breast cancer to improve health-related quality of life: A systematic review. Quality of Life Research, 26, 2573-2592. [Google Scholar]
  10. Duijts, SFA., & Spelten, ER. (2021). Cancer survivorship issues: Dissemination and translation of evidence-based knowledge. Cancers (Basel), 13, 5794. [Google Scholar] [CrossRef]
  11. Fusco, N., Marchiò, C., Ghidini, M., & Scatena, C. (2021). Special issue: Molecular biomarkers in solid tumors. Genes, 12, 984. [Google Scholar] [CrossRef]
  12. Gillespie, TC., Sayegh, HE., Brunelle, CL., Daniell, KM., & Taghian, AG. (2018). Breast cancer-related lymphedema: Risk factors, precautionary measures, and treatments. Gland Surgery, 7, 379-403. [Google Scholar] [CrossRef]
  13. Grizzi, G., Ghidini, M., Botticelli, A., Tomasello, G., Ghidini, A., Grossi, F., Fusco, N., Cabiddu, M., Savio, T., & Petrelli, F. (2020). Strategies for increasing the effectiveness of aromatase inhibitors in locally advanced breast cancer: An evidence-based review on current options. Cancer Management and Research, 12, 675-686. [Google Scholar] [CrossRef]
  14. Hadizadeh, M., Mohaddes Ardebili, SM., Salehi, M., Young, C., & Mokarian, F. (2018). GJA4/Connexin 37 mutations correlate with secondary lymphedema following surgery in breast cancer patients. Biomedicines, 6, 23. [Google Scholar] [CrossRef]
  15. Invernizzi, M., de Sire, A., Venetis, K., Cigna, E., Carda, S., Borg, M., Cisari, C., & Fusco, N. (2022). Quality of life interventions in breast cancer survivors: State of the art in targeted rehabilitation strategies. Anticancer Agents in Medicinal Chemistry, 22, [Google Scholar] [CrossRef]
  16. Invernizzi, M., Corti, C., Lopez, G., Michelotti, A., & Despini, L. (2018). Lymphovascular invasion and extranodal tumour extension are risk indicators of breast cancer related lymphoedema: An observational retrospective study with long-term follow-up. BMC Cancer, 18, 935. [Google Scholar] [CrossRef]
  17. Invernizzi, M., de Sire, A., Carda, S., Venetis, K., Renò, F., Cisari, C., & Fusco, N. (2020a). Bone-muscle crosstalk in spinal cord injuries: Pathophysiology and implications for patients’ quality of life. Current Osteoporosis Reports, 18, 422-431. [Google Scholar] [CrossRef]
  18. Invernizzi, M., de Sire, A., Lippi, L., Venetis, K., & Sajjadi, E. (2020b). Impact of rehabilitation on breast cancer related fatigue: A pilot study. Frontiers in Oncology, 10, 556718. [Google Scholar] [CrossRef]
  19. Invernizzi, M., Kim, J., & Fusco, N. (2020c). Editorial: Quality of life in breast cancer patients and survivors. Frontiers in Oncology, 10, 620574. [Google Scholar] [CrossRef]
  20. Invernizzi, M., Michelotti, A., Noale, M., Lopez, G., & Runza, L. (2019). Breast cancer systemic treatments and upper limb lymphedema: A risk-assessment platform encompassing tumor-specific pathological features reveals the potential role of trastuzumab. Journal of Clinical Medicine, 8, 138. [Google Scholar] [CrossRef]
  21. Invernizzi, M., Runza, L., De Sire, A., Lippi, L., Blundo, C., Gambini, D., Boldorini, R., Ferrero, S., & Fusco, N. (2020d). Integrating augmented reality tools in breast cancer related lymphedema prognostication and diagnosis. Journal of Visualized Experiments, 156, e60093. [Google Scholar] [CrossRef]
  22. Maurer, T., Jaskulski, S., Behrens, S., Jung, AY., Obi, N., Johnson, T., Becher, H., & Chang-Claude, J. (2021). Tired of feeling tired–The role of circulating inflammatory biomarkers and long-term cancer related fatigue in breast cancer survivors. Breast, 56, 103-109. [Google Scholar] [CrossRef]
  23. Michelotti, A., Invernizzi, M., Lopez, G., Lorenzini, D., Nesa, F., de Sire, A., & Fusco, N. (2019). Tackling the diversity of breast cancer related lymphedema: Perspectives on diagnosis, risk assessment, and clinical management. Breast, 44, 15-23. [Google Scholar] [CrossRef]
  24. Nardin, S., Mora, E., Varughese, FM., D’Avanzo, F., Vachanaram, AR., Rossi, V., Saggia, C., Rubinelli, S., & Gennari, A. (2020). Breast cancer survivorship, quality of life, and late toxicities. Frontiers in Oncology, 10, 864. [Google Scholar] [CrossRef]
  25. Pagni, F., Guerini-Rocco, G., Schultheis, AM., Grazia, G., & Rijavec, E. (2019). Targeting immune-related biological processes in solid tumors: We do need biomarkers. International Journal of Molecular Sciences, 20, 5452. [Google Scholar] [CrossRef]
  26. Pal, M., Muinao, T., Boruah, HPD., & Mahindroo, N. (2021). Current advances in prognostic and diagnostic biomarkers for solid cancers: Detection techniques and future challenges. Biomedical Pharmacotherapy, 146, 112488. [Google Scholar] [CrossRef]
  27. Rick, O., Dauelsberg, T., & Kalusche-Bontemps, EM. (2017). Oncological Rehabilitation. Oncology Research and Treatment, 40, 772-777. [Google Scholar] [CrossRef]
  28. Smoot, B., Kober, KM., Paul, SM., Levine, JD., Abrams, G., Mastick, J., Topp, K., Conley, YP., & Miaskowski, CA. (2017). Potassium channel candidate genes predict the development of secondary lymphedema following breast cancer surgery. Nursing Research, 66, 85-94. [Google Scholar] [CrossRef]
  29. Sung, H., Ferlay, J., Siegel, RL., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71, 209-224. [Google Scholar] [CrossRef]
  30. Sunilkumar M, Finni CG, Lijimol AS, Rajagopal MR (2021). Health-related suffering and palliative care in breast cancer. Current Breast Cancer Reports, 1–6. DOI 10.1007/s12609-021-00431-1. [CrossRef]
  31. Vannorsdall, T., Ermiece Straub, D., Saba, C., Blackwood, M., Zhang, J., Stearns, K., & Smith, KL. (2021). Interventions for multidimensional aspects of breast cancer-related fatigue: A meta-analytic review. Supportive Care in Cancer, 29, 1753-1764. [Google Scholar] [CrossRef]
  32. Venetis, K., Piciotti, R., Sajjadi, E., Invernizzi, M., Morganti, S., Criscitiello, C., & Fusco, N. (2021). Breast cancer with bone metastasis: Molecular insights and clinical management. Cells, 10, 1377. [Google Scholar] [CrossRef]
  33. Zhong, L., Guo, L., Ye, Z., Zhang, S., & Huang, R. (2020). Exogenous dendritic cells aggravate atherosclerosis via P-selectin/ PSGL-1 pathway. Biocell, 44, 225-236. [Google Scholar] [CrossRef]
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