Elsevier

The Breast

Volume 48, Supplement 1, November 2019, Pages S44-S48
The Breast

Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC)1

https://doi.org/10.1016/S0960-9776(19)31122-1Get rights and content

Abstract

Breast cancer has been one of the last tumor types to see benefit from immunotherapies. Yet, immune infiltrates have been noticed for decades in primary breast cancers. Lately, quantity of tumor infiltrating lymphocytes (TILs) have been reported to have strong prognostic value in improving estimates of distant recurrence-free survival, disease-free and overall survival in early-stage triple negative BC (TNBC) treated with standard adjuvant/neoadjuvant chemotherapy (Level 1B evidence). Quantity, as a percentage of tumor stromal infiltration, is based on an evaluation by pathologists using light microscopy on H&E stained glass slides (see method at www.tilsinbreastcancer.org) [1], [2] at time of diagnosis (pre-treatment and in the residual disease post neoadjuvant chemotherapy). Whilst TILs are currently not used for treatment allocation, this is an active area of investigation. Combination of atezolizumab with nab-paclitaxel in a phase III study has recently seen success in terms of improved progression free and overall survival for the PD-L1 -positive population of metastatic TNBC in the first line/newly relapsed setting [3]. This has led to approval of atezolizumab for use in this setting. However, this population was only 41% of the trial population. Data in advanced breast cancer currently suggest requirement for enrichment of the population for preexisting anti-tumor immunity for benefit to PD(L)1 inhibition.

Checkpoint inhibitors are currently being investigated in the early-stage setting in a number of phase II/III trials in TNBC with various different anti- PD-1, PD-L1 and CTLA-4 agents. In this context, we will face issues of the best chemotherapy backbone, the possible detrimental role of steroids and growth factor support, risk of overtreatment, differences between PD-1 and PD-L1 inhibition and if we can use a biomarker to effectively escalate or de-escalate chemotherapy and/or use checkpoint inhibition in this setting.

Section snippets

Background

Triple negative breast cancer (TNBC) continues to hold the poorest prognosis of breast cancer subtypes with tumours displaying a highly proliferative, aggressive phenotype leading to high rates of both local and distant recurrence [4]. In addition to the aggressive nature of TNBC the lack of sensitivity to endocrine agents and limited targeted therapy options contribute to significantly shorter disease free and overall survival, making alternate therapeutic strategies highly sought after.

The

TILs in breast cancer

While breast cancers have traditionally been thought to be less immunogenic than other tumour types, immune infiltrates have been noticed in primary breast cancer specimens for many years leading to the introduction of immunotherapy into trials in both early and advanced breast cancers across all immunophenotypes.

It has been well established that the host microenvironment is an important factor in predicting response to immune checkpoint inhibition, with particular interest in tumour

Prognostic utility of TILs in early stage TNBC

With the evolving role of TILs as a biomarker of immune modulation of malignant cellular proliferation and prediction of response to immunotherapy there has been increasing interest in the potential for other ways to utilize this biomarker. Currently this is largely of interest in the clinical trial population but there is increasing evidence of prognostic utility in patients receiving standard adjuvant therapies following treatment for early breast cancer.

Data from large clinical trials has

Potential clinical utility of TILs in the adjvant setting

The prognostic information provided by the TIL biomarker is clear, and as such, given that other prognostic markers in breast cancer are routinely reported such as tumor size, Ki67, grade etc, it is reasonable to consider adding the TIL biomarker to routine pathological reports. Currently we do not recommend that clinicians change their treatment decision making based on the TIL biomarker. However it is conceivable that this may occur in the future. Small T1 tumors (T1a, b, Node negative)

TILs as a prognostic marker during neoadjuvant treatment of TNBC

Several studies of TILs in the setting of neoadjuvant chemotherapy have shown both the predictive and prognostic value of this marker. High TILs have been associated with higher rates of pathologic complete response (pCR) to neoadjuvant treatment across all breast cancer subtypes [12], [13]. Even estrogen receptor positive breast cancers, which usually have a paucity of TIL, have higher pCR rates in the presence of higher TILs. Similarly to in the adjuvant setting this relationship is linear

TILs in advanced (metastatic) TNBC

There has been not a huge amount of published literature on the clinical relevance of TILs in the prognostication and therapeutic decision making process in metastatic TNBC. Results from an in house series and the KEYNOTE 086 study [15], [16] confirm that the TIL content is significantly lower in metastatic disease samples compared with primary tumors. The KN86 study, higher levels of TILs were also observed in the first line PDL1 positive cohort B compared with the previously treated cohort B.

TILs and immunotherapy

The introduction of immune checkpoint inhibitors as standard therapy has significantly changed the treatment paradigms and prognosis of many types of malignancies.

Outcomes in patients with melanoma, lung, renal and many other cancers have dramatically improved with the development of immune checkpoint inhibitors and early biomarkers to guide their use. Despite this proven efficacy in many tumour types it is only recently that there has been strong evidence to support their use in breast cancer

Future directions

Moving forward, the availability of an affordable, reproducible biomarker to predict prognosis in early stage TNBC gives rise to the potential of clinical trial designs with in built stratification for immunogenic disease.

The possibility of a reliable prognostic marker paves the way for trials of de-escalation of cytotoxic chemotherapy in those with favourable prognostic features including high TILs with the addition of a checkpoint inhibitor and flags the potential need for escalation of

Conclusion

TILs are an easily reproducible, inexpensive prognostic biomarker that add robust information both independently and in addition to currently used clinicopathologic factors. They represent a surrogate for anti-tumour T cell-mediated immunity with quantities above 30% a favourable prognosis.

Consideration of routine incorporation of stromal TILs into standard staging and prognostic tools should be strongly considered. Incorporating TILs routinely into clinopathologic assessment at time of

Acknowledgements

Sherene Loi is supported by the National Breast Cancer Foundation (NBCF) of Australia and the Breast Cancer Research Foundation (BCRF), NY.

Conflicts of interest

Sherene Loi receives research funding to her institution from Roche-Genentech, BMS and Merck. She is a member (uncompensated) of the IMpassion130 study.

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This article was published as part of a supplement sponsored by St. Gallen Oncology Conferences.

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