Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC)1
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.
References (0)
Cited by (56)
The origins of resident macrophages in mammary gland influence the tumorigenesis of breast cancer
2022, International ImmunopharmacologyCitation Excerpt :In addition to the traditional pathological diagnosis and discrimination of breast cancer, more precise molecular classification (including ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor 2) and Ki-67 statuses) has promoted the treatment of breast cancer into a more precise and individualized therapy era [20–22]. However, special types of breast cancer, such as triple-negative breast cancer (TNBC), inflammatory breast cancer, and endocrine therapy-resistant breast cancer, continue to cause high mortality of patients [23–25]. Recently, the studies of immune checkpoints improved the application of its inhibitors of immune cells in tumor therapy and achieved positive feedback, including in breast cancer [26].
Mannose modified co-loaded zoledronic liposomes deplete M2-tumor-associated macrophages to enhance anti-tumor effect of doxorubicin on TNBC
2022, Journal of Drug Delivery Science and TechnologyCitation Excerpt :Breast cancer is the most common female cancer worldwide [1–3]. Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, which is negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor expressions, accounting for 15–20% of all breast cancer cases [1]. TNBC patients are non-responsive to therapies that target HER2 receptors or hormonal therapies due to their triple-negative status [2].
- 1
This article was published as part of a supplement sponsored by St. Gallen Oncology Conferences.