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. 2012 Feb 27:10:33.
doi: 10.1186/1479-5876-10-33.

Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes

Katy Milne  1 , Cheryl Alexander, John R Webb, Winnie Sun, Kristy Dillon, Steve E Kalloger, C Blake Gilks, Blaise Clarke, Martin Köbel, Brad H Nelson
Affiliations

Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes

Katy Milne et al. J Transl Med. .

Abstract

Background: The immune system strongly influences outcome in patients with ovarian cancer. In particular, the absolute lymphocyte count in peripheral blood (ALC) and the presence of tumor-infiltrating lymphocytes (TIL) have each been associated with favourable prognosis. However, the mechanistic relationships between ALC, TIL and prognosis are poorly understood. We hypothesized that high ALC values might be associated with stronger tumor immunity as manifested by increased TIL, decreased tumor burden and longer survival.

Methods: ALC values were collected from patient records ≥ 2 years before, during or after primary treatment for high-grade serous ovarian cancer (HGSC). Lymphocyte subsets were assessed in peripheral blood by flow cytometry. CD8+ and CD20+ TIL were assessed by immunohistochemistry.

Results: Overall, patients had normal ALC values two or more years prior to diagnosis of HGSC. These values were not predictive of disease severity or survival upon subsequent development of HGSC. Rather, ALC declined upon development of HGSC in proportion to disease burden. This decline involved all lymphocyte subsets. ALC increased following surgery, remained stable during chemotherapy, but rarely recovered to pre-diagnostic levels. ALC values recorded at diagnosis did not correlate with CD8+ or CD20+ TIL but were associated with progression-free survival.

Conclusions: Patients with high intrinsic ALC values show no clinical or survival advantage upon subsequent development of HGSC. ALC values at diagnosis are prognostic due to an association with disease burden rather than TIL. Therapeutic enhancement of ALC may be necessary but not sufficient to improve survival in HGSC.

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Figures

Figure 1
Figure 1
ALC declines upon development of HGSC in proportion to disease burden. Change in ALC from pre-diagnostic (preDx) to pre-treatment (preTx) levels according to (A) stage of disease (pelvic involvement encompasses Stage I and II disease, peritoneal involvement is seen in Stage III and IV patients), (B) surgical debulking status (no visible residual vs visible residual), or (C) presence of ascites. Statistical significance measured by Kruskal-Wallis ANOVA and Dunn's post test.
Figure 2
Figure 2
Flow cytometric analysis of lymphocyte subsets in blood from controls and HGSC patients in comparison to ALC. PBMCs from controls and cancer patients (pre-treatment) were stained for the indicated markers and run on a BD Influx Multi-channel Flow Cytometer. Mann-Whitney U tests were performed to examine the differences between controls and cancer patients with respect to (A) CD3+, (B) CD3 + CD4+, (C) CD4 + CD25 + FoxP3+, (D) CD3+ CD8+, (E) CD19 + CD20+, (F) CD3-CD56 + and (G) CD3+CD56 + lymphocytes and (H) ALC values for each group.
Figure 3
Figure 3
Relationship between ALC and clinical outcome in ovarian cancer. HGSC patients were stratified into high and low quartiles based on ALC values recorded (A) ≤ 2 years prior to HGSC diagnosis, or (B) just prior to treatment. Kaplan Meier analysis was performed to compare PFS between groups; significance was assessed with the log-rank test. N values represent the number of patients in the highest and lowest quartiles only, the middle 2 quartiles have been omitted; panel B has a higher n value as not all patients with pre-diagnostic ALCs available had pre-treatment values available.
Figure 4
Figure 4
Effect of surgery and chemotherapy on ALC and ANC and relationship to clinical outcome. Friedman test followed by Dunn's post test was used to analyze (A) ALC and (B) ANC values collected prior to diagnosis (PreDx), prior to surgical treatment (PreTx), immediately prior to chemotherapy (PreChem) and immediately prior to the 4th cycle of chemotherapy (MidChem). For ALC, only the change from the pre-diagnostic time point to pre-treatment was significant. For ANC, the only insignificant change was from the pre-treatment to pre-chemotherapy time points. (C) ALC values recorded at the mid point of chemotherapy are associated with prolonged PFS by Kaplan-Meier analysis. (D) Extent of ALC recovery at the mid-point of chemotherapy (relative to pre-diagnostic ALC) is not associated with PFS in suboptimally debulked patients by Kaplan-Meier analysis.
Figure 5
Figure 5
Relationship between ALC and (A) CD8+ and (B) CD20+ TIL. Tumors were scored as positive or negative for the indicated TIL subpopulations. Average ALC values recorded during chemotherapy were compared by Mann-Whitney U test.
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