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Researchers deem tumor-infiltrating lymphocytes valid prognostic biomarker in TNBC

Publish date: September 15, 2014

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Complexity, balance of different immune cells drive clinical outcome

For decades, pathologists have noted that most human tumors are infiltrated by lymphocytes. The clinical significance of tumor-infiltrating lymphocytes (TILs) came into focus over the past decade, with large studies of sufficient size to detect statistically significant correlations with survival. The strongest evidence for tumor infiltration by T cells and favorable clinical outcome has been established in colorectal carcinoma. Similar correlations have now been observed in essentially all tumor types, including melanoma, head and neck cancer, lung cancer, and others. Over the past year, three large studies have firmly established the clinical significance of TILs in breast cancer. The largest study followed clinical outcomes of 12,439 newly diagnosed breast cancer patients in the United Kingdom and Canada over the course of 10 years. The study showed a survival benefit of CD8-positive T cells within breast tumors in both triple-negative and ER-negative/HER2-positive patients. A survival benefit from CD8-positive T cells within triple-negative breast tumors was also shown in two additional studies: ECOG and FinHER studies representing an additional 1,491 patients analyzed.

Together, these studies firmly established the prognostic significance of tumor-infiltrating CD8-positive T cells in triple-negative and HER2-positive breast cancer. Furthermore, these studies also found that tumor-infiltrating CD8-positive T cells are predictive of clinical benefit from trastuzumab and anthracyclines. Thus, the presence of intratumoral CD8-positive T cells can help guide breast cancer patient management and should be included in routine pathologic examinations – a concept the authors called "immunoscore."

However, T cells are often exhausted and dysfunctional within the tumor microenvironment. Recent studies have shown that tumor-infiltrating T cells express several immune checkpoint molecules – including CTLA-4, PD-1, TIM-3, and LAG-3 – which when engaged with their counterligands (B7 and PDL-1, for example) – leads to inhibition of T-cell function. This spawned the development of antibodies to block immune checkpoint molecules, which have demonstrated exciting clinical efficacy. An anti–CTLA-4 antibody (ipilimumab, Yervoy) demonstrated efficacy in phase III clinical trials and was approved by the U.S. Food and Drug Administration for metastatic melanoma in 2011. Antibodies blocking PD-1, or its counterligand PD-L1, are under clinical development by at least seven companies. Phase II data show encouraging clinical responses and potentially less toxicities than anti–CTLA-4. Importantly, these immune checkpoint inhibitors led to survival curves that plateau at 15%-25%, raising the exciting possibility that some patients may be cured – by agents that act on the host immune system only. These results further strengthen the notion that the host immune system can respond to cancer, that the success of the endogenous antitumor immune response determines clinical outcome and response to even conventional therapies, and that this immune response can be further enhanced for clinical benefit.

Other immune cell types also infiltrate human tumors, including B, NK, and myeloid cells. The balance of these different immune cell populations within tumors – and tumor-draining lymph nodes (TDLNs) – likely drives clinical outcome. Future studies need to account for this additional complexity, which will be possible using novel flow cytometry and image analysis approaches. A deeper understanding of the interplay between different immune cell populations within tumors and TDLNs will uncover ways to enhance the total effect of cancer immunotherapies, including checkpoint inhibitors and adoptive T-cell therapy.

Dr. Peter P. Lee is Billy Wilder Endowed Professor and Chair, department of cancer immunotherapeutics and tumor immunology at the City of Hope Comprehensive Cancer Center, Duarte, Calif. Dr. Lee said he had no relevant financial conflicts.

FROM ANNALS OF ONCOLOGY AND JOURNAL OF CLINICAL ONCOLOGY

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Evidence continues to accumulate that a breast cancer patient’s immune system plays a role in the outcome from aggressive disease. According to recently published studies, the presence of tumor-infiltrating lymphocytes present at the time of diagnosis provides a fairly consistent biomarker of prognosis for triple-negative breast cancer, and possibly for HER2-positive breast cancer, and furthermore, may predict treatment benefit for some patients.

In an analysis of tumor samples from 12,439 women diagnosed with breast cancer, enrolled in four studies, the presence of cytotoxic T cells within ER-negative tumors was associated with a 21%-28% reduction in the relative risk of dying of breast cancer, depending on the location of the T cells, Dr. Raza Ali and associates reported online in Annals of Oncology.

Dr. Peter P. Lee

Just over one-fifth of the 12,439 patients died of breast cancer within 10 years of diagnosis; median survival was 9.57 years. Among those with ER-negative tumors, the presence of CD8-positive lymphocytes was independently associated with a reduced relative risk of death from breast cancer. The adjusted hazard ratio (HR) for the presence of CD8-positive lymphocytes within the tumor was 0.72 (95% confidence interval, 0.62-0.84; P = .00003) and, for lymphocytes within the stroma, the HR was 0.79 (95% CI, 0.67-0.93; P = .004), Dr. Ali of the Cancer Research U.K. Cambridge Institute, and associates reported (Ann. Oncol. 25:1536-43, 2014).

Overall, the presence of CD8-positive lymphocytes was not associated with breast cancer–specific survival in women with ER-positive breast tumors; however, in a subgroup analysis, the prognostic effect of lymphocytes within ER-positive tumors did differ by HER2 status (P [heterogeneity] = .006). The HR for lymphocytes within the ER-positive, HER2-positive tumors was 0.73 (95% CI, 0.56-0.96; P = .022) after adjustment for known prognostic factors.

Furthermore, there was evidence from the National Epirubicin Adjuvant Trial of greater benefit from anthracyclines in patients with CD8-positive tumors (HR = 0.60; 95% CI, 0.37-0.96) versus patients with CD8-negative tumors (HR = 1.47; 95% CI, 0.72-3.02; P [heterogeneity] = .039), Dr. Ali and associates said.

The investigators used immunochemistry to quantify both cytotoxic CD8-positive T cells, a potential biomarker for the tumor-associated immune response, and a protein, FOXP3, expressed on T-regulatory lymphocytes and a potential biomarker for an immunosuppressive tumor effect. They found no association between FOXP3 expression and breast cancer mortality, irrespective of ER status.

In another recent report, stromal lymphocyte infiltration was significantly correlated with distant recurrence and overall survival in patients with triple-negative breast cancer (TNBC). In the prospective-retrospective validation study, two blinded pathologists evaluated 506 randomly selected tumor samples from two prospective Eastern Cooperative Oncology Group adjuvant phase III clinical trials, Dr. Sylvia Adams and associates reported online in the Journal of Clinical Oncology.

Investigators looked for both intraepithelial tumor-infiltrating lymphocytes (TILs), defined as the percentage of lymphocytes in direct contact with the tumor cells, and stromal TILs, defined as the percentage of tumor stroma containing infiltrating lymphocytes. The majority of 481 evaluable cancers had lymphocyte infiltration, which was significantly more likely to be found in the stroma (80% had at least 10% stromal TILs) than in the intraepithelial area (15% had at least 10% intraepithelial TILs), Dr. Adams of New York University, New York, and associates reported.

After a median follow-up of 10.6 years, 107 events of distant recurrence and 142 deaths were reported. Investigators found higher stromal TIL scores were associated with a better prognosis; each 10-point increase in the stromal TIL score was associated with an 18% decrease in the risk of distant recurrence, and a 19% decrease in the risk of death (distant recurrence-free interval HR, 0.82; 95% CI, 0.68-0.99; P = .04; and overall survival HR, 0.81; 95% CI, 0.69-0.95; P =.01) the investigators reported (J. Clin. Onc. 2014 [doi:10.1200/JCO.2013.55.0491]).

The intraepithelial score correlated with both distant recurrence-free interval (DRFI) and overall survival (OS) but did not reach significance (DRFI: HR, 0.53; 95% CI, 0.25-1.09; P = .08; OS: HR, 0.64; 95% CI, 0.39-1.05; P = .08). Multivariable analysis confirmed stromal TILs to be an independent prognostic marker of DRFI and OS, the authors reported.

These accumulating data are prompting researchers to speculate on the addition of immune checkpoint inhibitors to breast cancer treatment regimens. In an editorial accompanying Dr. Adams’s report, Dr. Sherene Loi of the Peter MacCallum Cancer Centre, East Melbourne, Australia, wrote: "Given the correlation of programmed death ligand 1 (PD-L1 or CD274) with the presence of TILs, the most tantalizing question is whether current T-cell checkpoint inhibitors, such as anti–PD-1 (programmed cell death 1) antibodies, will be helpful in the treatment of TNBC, a subtype of breast cancer that is sorely in need of more effective therapies"(J. Clin. Onc. 2014 [doi:10.1200/JCO.2014.56.7677]).

Researchers deem tumor-infiltrating lymphocytes valid prognostic biomarker in TNBC

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