Escalation and de-escalation of treatments is of paramount importance in early breast cancer (1). However, prediction of local or distant failure risk is needed to achieve a personalized medicine. Traditional clinical and pathological features (i.e. nodal status, Ki67%, grading, etc.) are not always able to actually predict disease relapse, especially in ER+ early breast cancer (2, 3). For this reason to predict the risk and address proper treatments can be challenging. Genomic assays such as EndoPredict or OncoType DX are expensive, not widely available and their role in clinical practice is still controversial (4).

In the last decades the relevance of the host’s immune system has been highlighted as crucial in determining clinical outcomes in many cancers, including breast cancer (5, 6). The host immune response has shown a remarkable impact on cancer progression (7). In particular the density and spatial localization of CD8+ infiltrate within central core and invasive margins of tumor (evaluated by the Immunescore) are becoming important prognostic predictors, playing a role in the balance between tumor immune surveillance and escape (8). Tumor-infiltrating lymphocytes (TILs) support antitumor cytotoxic response and are favorable prognostic features along with low densities of immunosuppressive elements like neutrophils and myeloid-derived suppressor cells (9, 10).

Because of their accessibility, peripheral blood neutrophils and lymphocytes counts have gained a broad interest in cancer prognostication as surrogate markers of inflammation and immune response. Easily-gettable and affordable blood-derived inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), have recently demonstrated that the status of immunity often reflects survival outcomes (11). Some evidences suggested the role of these ratios in breast cancer too. In a recent meta-analysis, it was found that NLR has a significant prognostic effect on the overall and disease-free survival rates, suggesting that it could be a promising prognostic marker (12). Platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) are less frequently studied, but they may also be prognostically informative in breast cancer (13–15).

Despite such evidences, results remain discordant, probably due to the study design. Some studies focus on a single molecular subtype or evaluate preoperative blood-derived lymphocyte ratios in presence of specific clinical-pathological characteristics or settings (16). Furthermore, the follow-up period considered in the analyses is often relatively short. This observation is crucial when considering that luminal breast cancers carry a consistent long-term risk of recurrence (17). Finally, in the last years many studies focused on the predictive role of inflammatory biomarkers in breast cancer patients treated by neoadjuvant chemotherapy and generally affected by a specific molecular subtype breast cancer (18, 19). Therefore previous studies investigated small series and highly selected cohorts of patients with breast cancer, while there is a lack of large unselected cohorts of early breast cancer patients.

In the present study we assessed the role of preoperative blood-derived lymphocyte ratios (NLR, PLR, LMR) to predict local or distant relapse in 1,763 breast cancer patients reviewed retrospectively. In particular, the prognostic relevance of lymphocyte ratios was investigated in ER+ HER2- early breast cancers where risk stratification is more challenging.

This study shows that systemic lymphocyte ratios, as measured in preoperative blood samples, can be reliable and inexpensive markers of disease recurrence in an unselected cohort of breast cancer patients. In particular, patients with high NLR and PLR had a significantly shorter 5-years LRRFS and DMFS, while the ones with high LMR had longer survival outcomes. As expected, multivariate analysis associated other factors to poor prognosis: age at diagnosis, pT and pN status, and ER status. More importantly, as for ER+ HER2- early breast cancers not treated with chemotherapy, PLR and LMR were found to be independent predictors of 5-years LRRFS, and LMR predicted both LRRFS and DFS.

Lymphocyte ratios have drawn an increasing attention in different fields of medicine, as they can be easily assessable markers of inflammation and prognosis in several disorders. From a pathophysiological point of view, a state of systemic inflammation is associated to an increased tumor aggressiveness due to the pro-angiogenic oxidative state that favours the acquisition of a stem cell status as well as the impairment of DNA repair mechanisms. Multiple studies have shown that higher NLR is associated with poorer survival in metastatic breast cancer (21, 22) and a recent meta-analysis highlighted that higher NLR was associated with both worse DFS and overall survival (12). Several previous studies reported that higher NLR is also associated with more advanced and aggressive breast cancer (23, 24). For this reason, the ratios between neutrophils in blood and other leukocytes, as the NLR, have been suggested as a prognostic value in cancer (25, 26). NLR is higher in patients with a more advanced disease (24), and correlates with poor survival in many cancers (27). However, recent studies showed controversial evidences of NLR usefulness in hormone receptor-positive breast cancer (28, 29). NLR, simple and inexpensive biomarker, has been introduced as a significant prognostic factor in many tumor types (30). However, it has not been accepted in many clinical settings since neutrophilia can be the result of elevated granulopoiesis and, therefore, may not be considered as an adverse sign for cancer progression. Another reason is that neutrophilia is associated with poor clinical outcome in all cancers except for stomach cancer, in which case a high NLR is a marker of good prognosis (27).

In this study, we analyzed simultaneously NLR, PLR and LMR as potential inflammatory biomarkers, and all of them showed concordant prognostic results in terms of 5-years LRRFS in early breast cancer patients. Interestingly we did not observe any overlap between clinical risk assessment and NLR, PLR, LMR in the prediction of survival outcomes. This suggests that the information derived from inflammatory biomarkers is different and non-redundant with the clinical features of the tumor currently available. Indeed, preoperative lymphocyte ratios may be more related to the patient’s immune system rather than being associated with the tumor burden, especially in case of early breast cancers. Therefore, easy-gettable lymphocyte ratios from routine blood counts may provide precious prognostic data to be added to the standard clinical assessment of the tumor.

Regarding ER+ HER2- early breast cancer, we found that preoperative PLR and LMR are prognostic biomarkers of disease recurrence. This piece of data may be helpful in clinics, where failure of standard therapy (endocrine treatment and chemotherapy) is observed in a substantial portion of ER+ HER2- early breast cancers (31–33). Therefore, non-invasive, inexpensive and easy obtained circulating biomarkers may contribute to select those patients who will benefit from personalized and scaled-up adjuvant treatments.

The main strengths of this study are: the large cohort of patients presented, the data homogeneously collected, and the simultaneous assessment of different lymphocyte ratios. However there are some limitations and pitfalls worth mentioning. First, the time span of the registry is rather long, so cancer therapy, types, and prognosis might have changed over time. Secondly, our findings may have been biased by the retrospective nature of the study. Lastly, we did not evaluate the stromal TILs in the tumors. Literature data demonstrate a robust association between stromal TILs and better prognoses, in particular in triple negative and HER2+ breast cancers (34–36). In these breast cancer subtypes high levels of TILs are also associated with increased response to neoadjuvant and adjuvant chemotherapy (37–39). However, a defined prognostic and predictive role of TILs in luminal-like breast cancer is still debated, likely due to the biological heterogeneity of this breast cancer subtype (40, 41). As future perspective, further studies will be undertaken to quantify TILs in selected cohorts of early breast cancers, with the aim to correlate the systemic inflammatory biomarkers with the corresponding picture of the immune infiltrate in the tissue.

In conclusion, our data suggest that preoperative systemic inflammatory blood biomarkers could provide clinically relevant information regarding the risk of disease relapse in early breast cancer, especially in case of ER+ HER2- tumors generally considered as good prognosis. Further studies assessing the clinical suitability of these markers are required. Moreover, postoperative inflammatory biomarkers should also deserve attention to determine the course of some treatments, by assessing the changes occurring during treatments in appropriately designed prospective studies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Institutional Review Board of Istituti Clinici Scientifici Maugeri (No. 2213/2018). The patients/participants provided their written informed consent to participate in this study.

MT and FC contributed to conception and design of the study. MT, FP, SA, and VT organized the database and collected data. SA and CM analyzed the data. MT, SA, FS, and FC drafted the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Article processing fee was paid by Istituti Clinici Scientifici Maugeri IRCCS.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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