Gene expression signatures have shown promising both as prognostic as well as predictive tools in primary breast cancer, but they are not routinely used in clinical practice. Several explanatory reasons have been pinpointed, such as lack of statistical confidence, diversity in operational definitions, inclusion of unselected breast cancer populations, as well as the former lack of prospective biological sample collection in older cancer trials . One of the reasons worth underlining is the use of cell-line panels in the development of these signatures, precluding the influence that tumour microenvironment plays in human hosts. The answer may come from the interaction with the immune system.
The impact of immune infiltrates in breast cancer (BC) prognosis and therapy response started to draw attention about 20 years ago . But it was only until recently that studies on tumour-infiltrating lymphocytes (TILs) started to point in the same direction.
In the work recently published by Loi et al , the authors retrospectively assessed 2,009 paraffin-embedded tumour blocks prospectively collected within the BIG 02-98 randomised phase III adjuvant trial comparing sequential doxorubicin-docetaxel with their concurrent administration or no taxane in node-positive breast cancer patients. Efficacy data from this trial was also recently published at 8 years of median follow-up . The TIL percentage analysis was performed on full-face hematoxylin and eosin-stained sections (independently carried out by two pathologists). They used predefined standardised definitions of intratumoural lymphocytes, stromal lymphocytes and lymphocyte-predominant breast cancer. There were no major differences in clinicopathologic characteristics for the included patients, compared to the original cohort, except enrichment in HER2-positive disease. The main finding of this study was the statistically significant prognostic association of TILs in the ER-negative/HER2-negative BC subtype for both disease-free and overall survival. Stated differently, for every 10% increment in stromal and intratumoural lymphocytic infiltrations, there was a 15% and 17% reduction of risk for recurrence and 17% and 27% reduction of risk of death, respectively. Furthermore, regarding the predictive association of TILs, there is evidence of a differential in treatment response according to chemotherapy regimen but only in the HER2-positive BC subgroup, which benefited from anthracycline-only chemotherapy (Nota bene: trastuzumab was not part of the adjuvant treatment in BIG 02-98).
Hence, this study by Loi et al  establishes a significant association between increasing lymphocytic infiltration and a favourable prognosis in ER-negative/HER2-negative BC. It pioneered in presenting a predictive effect of the anthracycline-only regimen regarding this infiltrate in HER2-positive BC. There are, of course, strengths and limitations to mention. Consideration is needed accounting that adjuvant trastuzumab was still not standard-of-care at the time of study enrolment, which renders the interpretation of the results in the HER2-positive subgroup difficult within current approaches. Another issue of concern that could be raised respecting future applicability relates to the need of devising a less operator-dependent and widely reproducible histopathological method for analysing TILs. The central review of pathological data, the prospective biobanking of samples and mature disease-free survival and overall survival data are strengths of this study, although additional validation is necessary.
These findings accumulate with previous work done by Denkert at al  that has shown pretherapeutical immunological infiltrate as being predictive for response to neoadjuvant treatment. Noteworthy, is the fact these data contradict most gene expression signatures that frequently identify the subgroups of good prognosis as being the low-proliferating tumours (luminal A and luminal B tumours). The former are chiefly constituted by a large module of proliferation genes. Furthermore, a recent metanalysis showed that the addition of an immune module to clinicopathologic characteristics enhances the predictive accuracy for pathologic complete response in the HER2-positive subtype .
Combined, these results constitute the proof-of-concept of the immunogenic cell death modality, by which the response to chemotherapy depends on an immunological reaction mounted against the inflammatory process generated by dying cancer cells during chemotherapy . This may be a key factor for therapeutic success. Research is needed in the immunological compartment of tumour microenvironment and the incorporation of these concepts in the biomarker development and design of clinical trials to come is warranted. Paget’s “seed and soil” hypothesis for metastases already highlighted the importance of the microenvironment for cancer. More and more we need to consolidate the concept in early disease too.
- Do you believe these findings can pave the way to an immunologic modulation of breast cancer treatment?
- In your opinion could the immunologic interplay be the missing piece of the puzzle to reach a therapeutic breakthrough in breast cancer treatment?
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