Markers of inflammation as predictors of efficacy of trastuzumab therapy in HER2-positive metastatic breast cancer patients
Abstract
Inflammatory indexes correlate with the effectiveness of therapy and prognosis of many cancer types. Our study aimed to identify independent predictors of the efficacy of trastuzumab therapy affecting progression-free survival (PFS) and overall survival (OS) in patients with HER2-positive metastatic breast cancer (mBC). The retrospective study included 78 HER2-positive mBC patients treated with trastuzumab at Sumy Regional Clinical Oncology Center. The baseline clin i copathological characteristics including age, number of metastases, menopausal status, hormonal status, trastuzumab-containing regimen, and inflammatory indexes, such as neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), platelet to lymphocyte ratio (PLR) and pan-immune-inflammation value (PIV) , were collected. Cut-off values of inflammatory markers were determined by ROC analysis. AUC ≥0.7 was considered statistically significant. Factors affecting PFS and OS were determined using the multivariate Cox proportional hazard model. Response to treatment was assessed every 2-3 cycles. Low PLR and trastuzumab plus chemotherapy regimen correlated with a high disease control rate. Multivariate analysis assessed the prognostic impact of age, number of metastases, menopausal status, hormonal st a tus, trastuzumab-containing regimen, and inflammatory indexes on PFS and OS in HER2-positive mBC patients. Trast u zumab-containing regimen and PLR were independent predictors of PFS. Patients who received trastuzumab plus chem o therapy and whose PLR before treatment was low had significantly better PFS. For OS, multivariate analysis showed the same results. Low PLR and trastuzumab plus chemotherapy regimen were independent predictors of OS. Low PLR is associated with better PFS, OS, and a high disease control rate. PLR may be an effective marker for identifying the cand i dates who most benefit from trastuzumab. Compared with trastuzumab monotherapy, the combination of trastuzumab and chemotherapy correlates with longer PFS and OS in patients with HER2-positive mBC.References
Al Sukhun, S., Temin, S., Barrios, C. H., Antone, N. Z., Guerra, Y. C., Chavez-MacGregor, M., Chopra, R., Danso, M. A., Gomez, H. L., Homian, N. M., Kandil, A., Kithaka, B., Koczwara, B., Moy, B., Nakigudde, G., Petracci, F. E., Rugo, H. S., El Saghir, N. S., & Arun, B. K. (2024). Systemic treatment of patients with metastatic breast cancer: ASCO resource-stratified guideline. JCO Global Oncology, 10, e2300285.
Blanchette, P. S., Desautels, D. N., Pond, G. R., Bartlett, J. M. S., Nofech-Mozes, S., Yaffe, M. J., & Pritchard, K. I. (2018). Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab. Breast Cancer Research and Treatment, 170(1), 169–177.
Chen, L., Kong, X., Yan, C., Fang, Y., & Wang, J. (2020). The research progress on the prognostic value of the common hematological parameters in peripheral venous blood in breast cancer. OncoTargets and Therapy, 13, 1397–1412.
Cozzolino, M., Cocco, S., Piezzo, M., Celia, G., Costantini, S., Abate, V., Capone, F., Barberio, D., Girelli, L., Cavicchiolo, E., Ascierto, P. A., Madonna, G., Budillon, A., & De Laurentiis, M. (2021). A psychosocial genomics pilot study in oncology for verifying clinical, inflammatory and psychological effects of mind-body transformations-therapy (MBT-T) in breast cancer patients: Preliminary results. Journal of Clinical Medicine, 10(1), 136.
Ding, N., Huang, J., Li, N., Yuan, J., Wang, S., & Xiao, Z. (2020). Roles of neutrophil/lymphocyte ratio in prognosis and in differentiation of potential beneficiaries in HER2-positive breast cancer with trastuzumab therapy. BMC Cancer, 20(1), 235.
Faria, S. S., Costantini, S., de Lima, V. C. C., de Andrade, V. P., Rialland, M., Cedric, R., Budillon, A., & Magalhães, K. G. (2021). NLRP3 inflammasome-mediated cytokine production and pyroptosis cell death in breast cancer. Journal of Biomedical Science, 28(1), 26.
Heinrich, B., & Korangy, F. (2022). Plasticity of innate lymphoid cells in cancer. Frontiers in Immunology, 13, 886520.
Imamura, M., Morimoto, T., Egawa, C., Fukui, R., Bun, A., Ozawa, H., Miyagawa, Y., Fujimoto, Y., Higuchi, T., & Miyoshi, Y. (2019). Significance of baseline neutrophil-to-lymphocyte ratio for progression-free survival of patients with HER2-positive breast cancer treated with trastuzumab emtansine. Scientific Reports, 9(1), 1811.
Isogai, A., Kotani, H., Sawaki, M., Hattori, M., Yoshimura, A., Kataoka, A., Nozawa, K., Ozaki, Y., Endo, Y., Nakakami, A., Komaki, R., & Iwata, H. (2023). Single-dose trastuzumab monotherapy achieved pathological complete response (pCR) in a patient with HER2-positive breast cancer: A case report. Surgical Case Reports, 9(1), 112.
Ji, W., & Guo, W. (2023). Male accessory breast cancer successfully treated with single-agent Trastuzumab: A case report. American Journal of Men's Health, 17(3), 15579883231171010.
Johnson, K. E., Ceglowski, J. R., Roweth, H. G., Forward, J. A., Tippy, M. D., El-Husayni, S., Kulenthirarajan, R., Malloy, M. W., Machlus, K. R., Chen, W. Y., Italiano Jr, J. E., & Battinelli, E. M. (2019). Aspirin inhibits platelets from reprogramming breast tumor cells and promoting metastasis. Blood Advances, 3(2), 198–211.
Laface, C., Ricci, A. D., Vallarelli, S., Ostuni, C., Rizzo, A., Ambrogio, F., Centonze, M., Schirizzi, A., De Leonardis, G., D'Alessandro, R., Lotesoriere, C., & Giannelli, G. (2024). Autotaxin-Lysophosphatidate axis: Promoter of cancer development and possible therapeutic implications. International Journal of Molecular Sciences, 25(14), 7737.
Ligorio, F., Fucà, G., Zattarin, E., Lobefaro, R., Zambelli, L., Leporati, R., Rea, C., Mariani, G., Bianchi, G. V., Capri, G., de Braud, F., & Vernieri, C. (2021). The pan-immune-inflammation-value predicts the survival of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer treated with first-line Taxane-Trastuzumab-Pertuzumab. Cancers, 13(8), 1964.
Mandó, P., Rivero, S, G., Rizzo, M. M., Pinkasz, M., Levy, E. M. (2021). Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era. Breast, 60, 15–25.
McFarland, D. C., Doherty, M., Atkinson, T. M., O'Hanlon, R., Breitbart, W., Nelson, C. J., & Miller, A. H. (2022). Cancer-related inflammation and depressive symptoms: Systematic review and meta-analysis. Cancer, 128(13), 2504–2519.
Nicolò, E., Gianni, C., Pontolillo, L., Serafini, M. S., Munoz-Arcos, L. S., Andreopoulou, E., Curigliano, G., Reduzzi, C., & Cristofanilli, M. (2024). Circulating tumor cells et al.: Towards a comprehensive liquid biopsy approach in breast cancer. Translational Breast Cancer Research, 5, 10.
Nolan, L., Davey, M. G., Calpin, G. G., Ryan, É. J., & Boland, M. R. (2024). Risk of locoregional recurrence after breast cancer surgery by molecular subtype – a systematic review and network meta-analysis. Irish Journal of Medical Science, 2024, in press.
Ogiya, R., Niikura, N., Kumaki, N., Bianchini, G., Kitano, S., Iwamoto, T., Hayashi, N., Yokoyama, K., Oshitanai, R., Terao, M., Morioka, T., Tsuda, B., Okamura, T., Saito, Y., Suzuki, Y., & Tokuda, Y. (2016). Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Science, 107(12), 1730–1735.
Otsuka, R., Hayashi, H., Uesato, M., Hayano, K., Murakami, K., Toyozumi, T., Matsumoto, Y., Kurata, Y., Nakano, A., Takahashi, Y., Arasawa, T., & Matsubara, H. (2023). Inflammatory and nutritional indices as prognostic markers in elderly patients with gastric cancer. Anticancer Research, 43(11), 5261–5267.
Passardi, A., Azzali, I., Bittoni, A., Marisi, G., Rebuzzi, F., Molinari, C., Bartolini, G., Matteucci, L., Sullo, F. G., Debonis, S. A., Gallio, C., Monti, M., Valgiusti, M., Muratore, M., Rapposelli, I. G., Ulivi, P., & Frassineti, G. L. (2023). Inflammatory indices as prognostic markers in metastatic colorectal cancer patients treated with chemotherapy plus Bevacizumab. Therapeutic Advances in Medical Oncology, 15, 1–13.
Piddubnyi, A., Kolomiiets, O., Danilchenko, S., Stepanenko, A., Moskalenko, Y., & Moskalenko, R. (2023). The prospects of using structural phase analysis of microcalcifications in breast cancer diagnostics. Diagnostics, 13(4), 737.
Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., & Norton, L. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. The New England Journal of Medicine, 344(11), 783–792.
Smorodska, O., Moskalenko, Y., Kononenko, М., & Ivanov, S. (2022). Inflammation indexes as predictors of disease recurrence in patients with surgically resected non-small cell lung cancer. Eastern Ukrainian Medical Journal, 10(4), 379–388.
Stoiber, D., & Assinger, A. (2020). Platelet-leukocyte interplay in cancer development and progression. Cells, 9(4), 855.
Tang, Y., Qian, C., Zhou, Y., Yu, C., Song, M., Zhang, T., Min, X., Wang, A., Zhao, Y., & Lu, Y. (2023). Activated platelets facilitate hematogenous metastasis of breast cancer by modulating the PDGFR-β/COX-2 axis. iScience, 26(9), 107704.
Vogel, C. L., Cobleigh, M. A., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L., Slamon, D. J., Murphy, M., Novotny, W. F., Burchmore, M., Shak, S., Stewart, S. J., & Press, M. (2023). Efficacy and safety of Trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. Journal of Clinical Oncology, 41(9), 1638–1645.
Vynnychenko, O. I., & Moskalenko, Y. V. (2024). Prognostic impact of body mass index on metastatic HER2-positive breast cancer survival. Ukrainian Journal of Radiology and Oncology, 32(3), 363–376.
Xie, L., Fang, J., Yu, J., Zhang, W., He, Z., Ye, L., Wang, H. (2023). The role of CD4+ T cells in tumor and chronic viral immune responses. MedComm, 4(5), e390.
Zhai, W. Y., Duan, F. F., Lin, Y. B., Lin, Y. B., Zhao, Z. R., Wang, J. Y., Rao, B. Y., Zheng, L., & Long, H. (2023). Pan-immune-inflammatory value in patients with non-small-cell lung cancer undergoing neoadjuvant immunechemotherapy. Journal of Inflammation Research, 16, 3329–3339.
Zhang, X., Leng, J., Zhou, Y., Mao, F., Lin, Y., Shen, S., & Sun, Q. (2021). Efficacy and safety of anti-HER2 agents in combination with chemotherapy for metastatic HER2-positive breast cancer patient: A network meta-analysis. Frontiers in Oncology, 11, 731210.
Zuo, X. X., Yang, Y., Zhang, Y., Zhang, Z. G., Wang, X. F., & Shi, Y. G. (2019). Platelets promote breast cancer cell MCF-7 metastasis by direct interaction: Surface integrin α2β1-contacting-mediated activation of Wnt-β-catenin pathway. Cell Communication and Signaling, 17(1), 142.
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