Inflammatory Blood Markers in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

The Prognostic and Predictive Role of Inflammatory Blood Markers in Early and Locally Advanced Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Breast cancer is the most threatening disease in women. Neoadjuvant chemotherapy is a commonly used for the treatment. Inflammation plays an important role in tumor proliferation, metastasis, and resistance to chemotherapy. Inflammatory blood markers (IBM) reflect the balance between host inflammatory and immune status. Different IBM have been reported as prognostic factors for survival and predictive factors for pathological complete response and toxicity. Our aim to evaluate these IBM in breast cancer patients receiving neoadjuvant chemotherapy.

Inflammation, recognized as one of the 10 hallmarks of cancer (seventh hallmark of cancer), contributes to tumour proliferation, angiogenesis, metastasis, and resistance to chemotherapy. In general, white blood cell count reflects an individual's systemic and/or local inflammatory status. Neutrophils are known to regulate the tumour microenvironment and produce cytokines, chemokines, and growth factors that may promote angiogenesis as well as tumour cell proliferation and migration. The M2 phenotype tumour-associated macrophages (TAMs) deriving from circulating monocytes exist within the tumour microenvironment and promote metastasis and immunosuppression. It was reported that peripheral monocyte count was associated with the density of the TAMs, and high absolute monocyte count predicted poor survival in cancer patients. Platelets are other cells contributing to cancer-favoured inflammation by various mechanisms. For example, the activated platelets inhibit the interaction between tumour cells and cytolytic immune cells by forming a layer around tumour cells and support tumour growth via the secretion of several factors such as TGF-β. Hence, high platelet counts were reported to be associated with adverse outcomes in breast cancer. In contrast, lymphocytes are responsible for antitumor-specific immune response including T-lymphocyte tumour infiltration and cytotoxic T-lymphocyte-mediated antitumor activity.

Inflammatory blood markers (IBM) have emerged as potential prognostic factors for survival in different types of cancers including breast cancer, as well as predictive factors for histological response after neo-adjuvant chemotherapy. IBM include leucocyte count, lymphocyte count, neutrophil count, and ratios such as platelet to lymphocyte ratio (PLR) or neutrophil to lymphocyte ratio (NLR), and monocyte to lymphocyte ratio (MLR). Starting from these findings, NLR, MLR, and PLR, indices reflecting the balance between inflammation and immunoreaction in cancer, were reported to have predictive value in NAC response in many breast cancer studies.

There are conflicting reports about which index provides the best prediction for the efficacy of NAC in breast cancer. For example, Eren et al. reported that NLR was the only independent predictive factor of pathological complete response (pCR) among blood-derived inflammation markers in multivariate analysis. In another study conducted by Peng et al., multivariate analysis of 808 breast cancer patients showed that the lymphocyte-monocyte ratio was the only independent predictive factor for the efficacy of NAC among these inflammatory markers. In addition, Hu et al. stated that PLR had superior efficacy to NLR in predicting NAC response.

Different studies tried to integrate different peripheral blood immune cells as, Jiang et al., that used systemic immune-inflammation index (SII); is based on neutrophil (N), platelet (P) and lymphocyte (L) counts, and stated that prognostic utility of (SII) was superior to that of NLR and PLR. Also Dong et al used the systemic inflammation response index (SIRI); an integrated indicator based on the counts of peripheral venous blood neutrophils(N), monocytes(M) and lymphocytes(L), and stated the prognostic value of the (SIRI) for pCR was superior to that of NLR.

Pan-Immune-Inflammation-Value (PIV) is a new blood-based biomarker integrating different peripheral blood immune cell subpopulations-neutrophil, platelet, monocyte, and lymphocyte. Due to its potential to represent comprehensively patient's immunity and systemic inflammation, PIV was proposed as a stronger predictor of outcomes in cancer patients receiving cytotoxic chemotherapy, immunotherapy, and targeted therapy. Recently, Ligorio reported that PIV was firmly associated with survival and outperformed NLR, PLR, and MLR in predicting survival in patients with HER-2 positive advanced breast cancer.

Sahin et al., stated that pre-treatment PIV seems as a predictor for pCR and survival, outperforming NLR, MLR, PLR in Turkish women with breast cancer who received NAC.

Some studies stated that the SIRI and SII had no significance on toxicities like peripheral neuropathy and neutropenia. However, other studies reported NLR as predictive factor for febrile neutropenia.

These integrated indicators may fully reflect the balance between host inflammatory and immune status compared with NLR, MLR and PLR and other conventional haematological parameters.

These conflicting results have raised the need for a study to evaluate these inflammatory blood markers in patients with breast cancer receiving neo adjuvant chemotherapy.

Inclusion Criteria:

• Patients aged 18 years old or more.
• Histologically proven invasive breast cancer.
• Above cT1 stage, any N Stage with no distant metastasis M0.
• All subtypes are included, either HR (ER, PR) positive or negative, HER2 positive or negative.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≤ 2.
• Patients who completed their systemic neoadjuvant therapy.
• Available baseline complete blood picture before starting treatment.

Exclusion Criteria:

• Second malignancy.
• Patients with early breast cancer cT1 (≤ 2 cm) N0.
• Metastatic patients M1.
• Patients with systemic inflammatory diseases or autoimmune diseases (Type I Diabetes mellitus, Systemic Lupus Erytheromatosis, Rheumatoid Arthritis, Sjogren's syndrome, Behcet disease).
• Pregnancy-related breast cancer.
• Patients with chronic diseases (liver cirrhosis, or end-stage renal disease).
• Patients on systemic steroids as well as those under NSAIDS or other immunomodulators (as Methotraxate, Tacrolimus and Cyclosporine).
• Patient who received radiotherapy or endocrine or targeted therapy prior to neoadjuvant chemotherapy.
• Patients who started but didn't complete neoadjuvant systemic therapy.
• Patients who didn't undergo surgery after neoadjuvant systemic therapy.