Derived neutrophil-to-lymphocyte ratio predicts DFS in early breast cancer

COPENHAGEN, Denmark — The derived neutrophil-to-lymphocyte ratio predicted shorter DFS among women with HER-2–enriched and nonluminal intrinsic subtypes of early breast cancer, according to retrospective study results presented at the European Society for Medical Oncology Congress.

Perspective from Nadia Harbeck, MD

The ratio also appeared associated with shorter DFS and OS among women with estrogen receptor–positive, PR–negative tumors.

“This is the first study exploring the prognostic role of derived neutrophil-to-lymphocyte ratio in the adjuvant treatment of early breast cancer patients,” Alberto Ocana Fernandez, MD, of the translational research unit at Albacete University Hospital in Spain, said during a presentation.

Prior research established the association between high levels of host inflammation and poorer outcomes of patients with several types of solid tumors.

Ocana Fernandez and colleagues assessed the prognostic role of derived neutrophil-to-lymphocyte ratio in certain women with early breast cancer included in the GEICAM/9906 trial, a randomized phase 3 study designed to compare adjuvant FEC chemotherapy — which consists of 5-FU, epirubicin and cyclophosphamide — with FEC chemotherapy plus paclitaxel in patients with breast cancer who had axillary involvement.

Researchers calculated the ratio of neutrophils divided by the difference between total leukocytes and neutrophils measured in peripheral blood prior to chemotherapy.

DFS served as the primary endpoint, and OS served as a secondary endpoint.

Investigators used univariable Cox regression to evaluate the prognostic and predictive value of the ratio. They also analyzed subgroups characterized by PAM50 subtype and hormonal receptor expression.

The analysis included 1,243 patients (median age, 50 years; range, 23-76) from 65 sites in Spain. Two-thirds (66%) of patients had PAM50 subtype determination available; of these patients, 22% had luminal A tumors, 21% had luminal B tumors, 14% had HER-2–enriched tumors, 6% had basal-like tumors and 3% had normal-like tumors.

Nearly half (47%) of tumors were ER positive/PR positive, whereas 13% were ER negative/PR negative.

Median follow-up was 10 years.

Median derived neutrophil-to-lymphocyte ratio was 1.35 (interquartile range, 1.08-1.71).

Among women with HER-2–enriched tumors, a ratio greater than the median appeared significantly associated with shorter DFS (HR = 1.63; 95% CI, 1.04-2.54).

Among women with nonluminal tumors, a ratio greater than the median appeared associated with shorter DFS (P = .02), as did a high ratio explored by quartiles (P = .03).

Among women with ER–negative, PR–negative tumors, a high ratio determined by quartiles appeared associated with shorter DFS (P < .001) and OS (P = .007).

“The [ratio] values are lower than those described in metastatic scenarios, probably due to an [increased] inflammatory response in ... advanced disease,” Ocana Fernandez said. “Multivariate analysis and additional studies are necessary to confirm the independent prognostic value of derived neutrophil-to-lymphocyte ratios in different subtypes of early breast cancer patients.” – by Mark Leiser

For more information: Ocana Fernandez A, et al. Abstract 145O. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.

Disclosure: The GEICAM Spanish Breast Cancer Group provided funding for this study. The researchers report no relevant financial disclosures.

Perspective

Nadia Harbeck, MD

It is important to mention that no adjuvant trastuzumab (Herceptin, Genentech) was given [because the study on which the data are based was designed prior to the agent’s approval], and that these values were measured pretreatment.

I hadn’t heard about this biomarker very much, so I began asking myself three questions: Is this a breast cancer–specific phenomenon? Is there an easy explanation? And, is there any clinical utility for this factor?

In the literature, there is quite a bit of data on neutrophil-to-lymphocyte ratio in breast cancer, and they show a high ratio is an adverse prognostic factor for OS.

There also is a range of literature looking at this ratio in solid tumors. It also shows a high ratio is an adverse prognostic factor, so there is consistency in the data beyond what we heard [in this study].

There actually is a very straightforward reason. Neutrophils can release TIMP-free matrix metalloproteinase 9, and this can induce an angiogenic switch that is critical for tumor progression.

So what does this mean? I think this abstract and other literature very nicely show that the host matters.

This is an easily accessible biomarker. However, there are some challenges.

There is no optimal threshold. If you look at the literature, there are quartiles and medians, but there is no cutoff that can easily be used in the clinic. Also, the prognostic impact has not been demonstrated.

Is this a static biomarker that is measured once — like in this abstract, in which it was measured pretherapeutically — or is it a dynamic biomarker, which would be easily implemented because it is so easy to access the neutrophil count?

For now, the neoadjuvant setting may be quite a good setting for its use. We need biomarker validation, and whether it is a therapeutic target remains to be determined.

Nadia Harbeck, MD

Head of the Breast Centre

University of Munich

Munich, Germany

Disclosures: HemOnc Today could not confirm Harbeck’s relevant financial disclosures at the time of reporting.