https://orcid.org/0000-0003-3894-4552
Abstract
Background
The predictive value of tumor-infiltrating lymphocytes (TILs) on the benefit from radiotherapy (RT) remains unclear. Our aim was to investigate the association between TILs and post-mastectomy RT (PMRT) regarding the risk of recurrence and survival in a randomized cohort.
Material and methods
Stromal TILs were histologically estimated in 1011 tumors from high-risk breast cancer (BC) patients from the DBCG82bc trial. Patients were diagnosed between 1982 and 90, treated with total mastectomy and partial axillary lymph node dissection, randomized to ± PMRT followed by adjuvant systemic treatment. A competing risk model, Kaplan–Meier analysis and multivariate Cox regression analysis were used for correlating TILs and clinical outcome.
Results
106 of 1011 patients (10.5%) showed high TILs using a 30% cut-off. In multivariate regression analysis, a high level of TILs was an independent factor associated with lower risk of distant metastasis (DM) and improved overall survival (OS), but without association with loco-regional control. High TILs were associated with a significantly greater OS after PMRT at 20 years compared to low TILs (8% improvement for low TILs (23% to 31%) vs. 22% for high TILs (26% to 48%), interaction-test: p = 0.028). The association between TILs and PMRT was more pronounced among estrogen-receptor negative (ER–) tumors, and patients having ER–/low TILs tumors showed no OS benefit from PMRT at 20 years (–4% improvement for low TILs (28% to 24%) vs. 23% for high TILs (20% to 43%). A similar trend in the association between high TILs and reduced risk of DM after PMRT was seen.
Conclusion
High TILs predict improved OS from PMRT in BC patients, and the association appeared especially strong for ER– tumors. A trend in the association between high TILs and reduced risk of DM after PMRT was seen. These findings may indicate that RT triggers an immune response inducing a systemic effect outside the treatment field.
Introduction
Tumor-infiltrating lymphocytes (TILs) represent a surrogate marker for the adaptive immune system. Around 10–11% of breast cancers (BC) have been found to contain a high number of TILs, and these are usually more aggressive and highly proliferative, estrogen receptor (ER) negative tumors with either a triple-negative (TN) or HER2 positive (HER2+) phenotype. Both ER-positive (ER+) (luminal) and ER-negative (ER–) (non-luminal) cancers can, however, show low, intermediate and high levels of TILs [Citation1].
A high level of TILs has been associated with improved recurrence-free- and overall survival (OS) especially in patients with TN and HER2+ breast cancers [Citation2–4]. An adverse prognostic effect of high TILs has on the other hand been described in patients with ER+/HER2 negative (HER2–), luminal tumors, which is suggested to be related to immunomodulating effects of anti-estrogen treatment [Citation5]. Furthermore, a high level of TILs is more predictive of response to neoadjuvant chemotherapy in all subtypes of breast cancer [Citation5]. TILs have also been investigated as a predictive marker of response to PD-1/PD-L1 inhibitors in BC patients, and it has been proposed to add evaluation of TILs to PD-L1 expression to strengthen the predictive value of the latter [Citation6].
The association between TILs and radiotherapy (RT) is less well-described, and the effect of RT has complex and opposing effects on the immune system including upregulation of immune checkpoints (e.g., PD-L1) contributing to a generalized immunosuppressive microenvironment [Citation7,Citation8]. The association has been examined in the SweBCG91RT trial of BC patients treated with breast-conserving surgery (BCS) and randomized to ±RT [Citation9,Citation10]. The findings indicated a positive association between high TILs and reduced risk of ipsilateral breast tumor recurrence (IBTR), suggesting that RT would be more beneficial in patients with low TILs [Citation9]. Currently, it is investigated in which way the delivery of RT may affect the immune response [Citation11–13]. This includes investigation of possible systemic effects of RT induced by local immune-priming effects resulting in the circulation of effector immune cells to distant sites, as well as how the immune response might be shaped and systemic effects induced by specific RT regimes (dose and fractionation) and combinations of RT with chemo- and/or immunotherapy [Citation13–16].
Loco-regional RT is aimed at eliminating tumor stem cells that may remain in the loco-regional area after surgery. After mastectomy, this will primarily encompass eradication of residual tumor cells located in the chest wall and regional lymph nodes. If left untreated, these residues may lead to local or distant recurrences (or a local recurrence may act as a nidus for distant recurrence) and eventually death from BC. Not all BC patients gain benefit from RT and some patients may only suffer the risk of RT associated early and late side-effects, including ischemic heart disease [Citation17,Citation18] and secondary cancer [Citation19]. The effect of RT on survival has further been shown to vary with tumor biology (e.g., ER, HER status), as aggressive tumors with a predilection of early metastatic seeding (e.g., TN and HER2+ BC) are less likely to achieve a survival benefit by RT through local control [Citation20]. A previous study of the DBCG82bc cohort (Danish Breast Cancer Group) showed a reduction of loco-regional recurrences (LRR) after PMRT among all BC subtypes, translating only into improved overall survival (OS) in patients with ER + and/or HER2– tumor [Citation20]. On the other hand, ER+/HER2– tumors, especially with a Luminal A subtype, are associated with a lower risk of LRR than the other subtypes [Citation21–23], and ongoing clinical trials, e.g., the DBCG Natural trial (ClinicalTrials.gov, NCT03646955) and the EXPERT trial (NCT02889874) are investigating the effect of omitting RT after BCS in selected patients with ER+/HER2– tumors.
Given the varying benefit of RT among BC patients, the risk of acute and late effects of RT and the decreasing LRR rate [Citation24–27], it is of utmost importance to refine the identification of patients with more or less benefit from RT and focus on the indirect systemic effects on distant metastasis (DM).
We have previously developed and validated a predictive gene-expression profile (DBCG-RT profile) capable of identifying patients with benefit from PMRT in the DBCG82bc cohort [Citation28]. The genes in the profile correlated with various parts of the immune system, e.g., inflammatory response, T-cell activation and differentiation and antigen-presenting.
Now, we aim to investigate the predictive value of TILs in terms of benefit from PMRT in pretreatment tumor material from the DBCG82bc cohort of high-risk BC patients randomized to RT or not and to examine if a possible association are dependent on the ER status.
Material and methods
Patients
The DBCG82bc cohort has been described in detail elsewhere [Citation29–32]. In brief, 3083 BC patients treated with mastectomy and partial axillary dissection and diagnosed in the period 1982–1990 were included. All patients received systemic therapy according to menopausal status. Premenopausal women were treated with cyclophosphamide, methotrexate and fluorouracil (CMF), and postmenopausal women with tamoxifen. All patients were under the age of 70 and considered to be at high risk of recurrence due to positive lymph nodes and/or tumor size >5 cm and/or invasion in the skin or pectoral fascia. A median of 7 axillary lymph nodes was removed.
From a total of 1011/3083 patients, tumor-containing paraffin blocks collected for previous studies of the DBCG82bc cohort [Citation20,Citation28] were available and contained sufficient invasive carcinoma to be included in the current study of TILs, as depicted in the CONSORT diagram (Supplemental Figure 1). A total of 932 pts. (92%) had more than 7 lymph nodes removed.
ER– and Progesterone (PR) receptor–, HER2–receptor status and Ki-67 index were available from immunohistochemical analysis (IHC) analyses on Tissue Micro Arrays (TMA) carried out as part of the previous studies [Citation20,Citation28]. For ER and PR, a cut-off of 1% was used (≥1%). HER2 evaluation followed the ASCO 2007 guidelines [Citation33] applicable at the time of analysis. For two patients, HER2 status was not available. A cut-off of 20% was used for separating high (≥ 20%) and low Ki-67 (<20%).
The evaluation of TILs was performed on Hematoxylin-Eosin stained, whole slides. The evaluation followed the recommendations from the TILs working group 2014 [Citation34] and was carried out by two observers independently (TT, HV). In short, TILs encompass both lymphocytes and plasma cells, and only stromal TILs within the borders of the invasive tumor were evaluated. The estimation was semiquantitative, assessing an average TILs score in the tumor area for the whole section with no evaluation of hotspots. Each TILs value describes the ‘area of stromal tissue occupied by TILs/total area of intra-tumoral stromal area’. TILs were recorded as a continuous variable, and hereafter, the amount of TILs were categorized into various 2- or 3-tier categorizations using different cut-offs (0–10%, 11–39%, ≥40%; 0–20%, 21–49%, ≥50%; <10% vs. ≥10%; <20% vs. ≥20%; <30% vs. ≥30%; <40% vs. ≥40%; <50% vs. ≥ 50%; <60% vs. ≥60%).
The interobserver agreement between the two raters in assessing TILs showed an intraclass correlation coefficient (ICC) including a 95% confidence interval (CI) above 0.70 and an overall concordance for all categories in the range of 0.84–0.97 (Supplemental Table 1). A cut-off value of 30% for distinguishing between low and high TILs was chosen for subsequent analyses since this cut-off was associated with the best combination of high Fleiss kappa value and an optimal concordance rate. This led to 106 patients (10.5%) being categorized as having tumors with high TILs levels and 905 (89.5%) with low TILs levels ().
Figure 1. Hematoxylin–eosin (HE) staining’s showing examples of tumors with (A) low level of stromal tumor-infiltrating lymphocytes (TILs) and (B) high level of TILs using a cut off of 30%.
The study was approved by The Central Denmark Region Committees on Health Research Ethics (journal no. 1-10-72-45-17), The Danish Data Protection Agency (journal no. 1-16-02-698-17), and reporting follows Recommendation for Tumor Marker Prognostic Studies (REMARK) criteria [Citation35].
Statistical analysis
Inter-observer agreement for the evaluation of TILs reported as a continuous score was assessed via the ICC calculated using a mixed model. No standard values for an acceptable agreement for ICC exist, but an ICC of >0.70 (including 95% CI > 0.70) has previously been used as an endpoint for a successful evaluation of TILs [Citation36,Citation37]. Fleiss kappa (for 2 raters) was used for assessing the inter-observer agreement, when evaluating TILs as categorical data [Citation38,Citation39], as well as concordance rates (=percentage of agreement between raters in predicting a low, (intermediate) or high level of TILs).
A competing risk model, Kaplan–Meier analysis and multivariate Cox regression analysis (MVA) were used for analyzing correlations between TILs and clinical outcome. The endpoints considered were LRR, DM and OS. LRR was defined as the appearance of ipsilateral chest wall failure (local) or ipsilateral axillary or supra/infraclavicular failure (regional). DM was defined as any failure outside the ipsilateral mammary region and the regional lymph nodes. The following events were competing with LRR: DM >1 month before LRR, contralateral breast cancer (CL) >1 month before LRR/DM, second primary cancer (SPC) >1 month before LRR/DM/CL, and death without any other event. The following events were competing with DM: CL >1 month before DM, SPC >1 month before DM/CL, and death. Patients alive with no events were censored at the last date of vital status/follow-up. Effects of competing risks were evaluated by fitting cumulative incidence functions, and cumulative probability curves were calculated and tested for differences. Survival outcome was calculated from the date of surgery. Cox uni- and multivariate regression analyses were performed, and assumptions of proportional hazards were tested graphically using log-minus-log plots. The MVA was stratified on ER status which did not show proportional hazards. Interaction tests were calculated on adjusted hazard ratios (HR) from the MVA (adj. interaction test) as well as on risk differences. The level of significance was 5% and all estimated p-values were two-sided. Statistical analysis was performed using STATA-version 16.1 (StataCorp, College Station, TX).
Results
shows the demographic, clinical and pathological characteristics of data for the patients included in the present study. Patients were equally distributed between the randomization arms (±PMRT). The level of TILs was significantly associated with malignancy grade, histology type and ER– and HER2 status, but not with age, menopausal status (protocol), tumor size or nodal status. For 1009 patients (99.8%), IHC defined subtypes could be constructed from ER–, PR–, HER2 status and Ki-67. Tumors with high as well as low TILs were found among all subtypes, though the distribution was statistically significantly different (Fischer exact test, p < 0.0001). As expected, high TILs were more frequently seen among non-luminal tumors (ER- and PR- tumors), whereas the majority of ER+/HER2– cancers showed low levels of TILs. High TILs were further associated with having a ‘high LRR risk’ score according to the DBCG-RT profile.
Table 1. Patient characteristics.
After a median follow-up time of 25 years, a total of 232 LRR and 580 DM were observed, corresponding to cumulative incidences of 23% and 58% for risk of LRR and DM, respectively. In the low TILs group, cumulative incidences were 22% (200/905) and 58% (525/905) for risk of developing LRR or DM, whilst cumulative incidences in the high TILs group were 30% (32/106) and 51% (55/106) for LRR and DM, respectively.
In a univariate analysis encompassing all 1011 patients, TILs level was not associated with either risk of LRR, DM or with OS (). However in an MVA, high TILs were associated with a significantly lower risk of DM (adj. HR= 0.62, CI: 0.46–0.83) and improved OS (adj. HR = 0.65, CI: 0.50–0.84), when adjusting for PMRT, menopausal status, T- and N-stage, histology type, malignancy grade and HER2 status and stratified by ER. An association between TILs and LRR was not found in MVA (adj. HR= 1.00, CI: 0.67–1.50).
Table 2. Uni- and multivariate Cox regression.
The MVA was repeated using 20% and 40% as cut-off values for low vs. high TILs. This led to similar results as for a 30% cut off with non-significant associations between TILs and LRR (20%; HR = 0.97 (0.67–1.39, p = 0.85 and 40%; HR-0.91 (0.59–1.42), p = 0.69), but significant associations with DM (20%; HR = 0.60 (0.47–0.78), p < 0.0001 and 40%; HR-0.65 (0.48–0.90), p = 0.0087) and OS (20%; HR = 0.70 (0.57–0.87), p = 0.0014 and 40%; HR-0.68 (0.51–0.90), p = 0.0065).
A significant positive association between high TILs and OS was observed after PMRT, illustrating the predictive value of TILs in terms of benefit from PMRT. For all clinical endpoints, a benefit from PMRT could be seen regardless of TILs level (). The reduced risk of LRR after PMRT was of similar size for patients with low and high TILs (24% vs. 26% difference at 20 years, ). A trend for greater reduction in risk of DM was seen (10% reduction for low TILs (63% to 53%) vs. 19% for high TILs (62% to 43%) at 20 years), but the adjusted interaction test was not significant (p = 0.28) (). A significantly greater OS benefit at 20 years after PMRT was, however, observed for patients with high TILs as compared to patients with low TILs in the tumor (8% improvement for low TILs (23% to 31%) vs. 22% for high TILs (26% to 48%)) with a significant adjusted interaction test (p = 0.028) (). The interaction test was only statistically significant with the chosen cut-off value of 30% and not using a 20% or 40% cut-off value.
Figure 2. Cumulative incidence proportion plots for (A,B) risk of loco-regional recurrence (LRR) and (C,D) risk of distant metastasis (DM) and Kaplan–Meier plots for (E,F) overall survival (OS) for all 1,011 patients divided according to level of tumor-infiltrating lymphocytes (TILs) and stratified according to randomization to post-mastectomy radiotherapy (PMRT) or not (red – PMRT, blue – no PMRT). Actuarial risks at 5, 10 and 20 years and risk difference in actuarial risks at 20 years with 95% confidence intervals are provided, as well as p-values for Log Rank tests for Kaplan–Meier estimates. Interaction tests between TILs and PMRT are stated for both adjusted Cox analysis and risk differences.
The association between TILs and PMRT appeared stronger among patients with ER- tumors. When stratifying the patients according to ER status, only patients with ER–/high TILs tumors showed benefit from PMRT in terms of OS, whereas patients with ER–/low TILs (207/1011) BC was seen to derive no benefit from PMRT (–4% improvement for low TILs (28% to 24%) vs. 23% for high TILs (20% to 43%)) (). The adjusted interaction test was non-significant (p = 0.092), but the difference in risk difference was 27% among ER– patients (interaction test (risk difference), p = 0.029) compared to 8% among ER + patients () and 14% in the total cohort (). The stratification according to ER status led to a limited number of patients in each group (except the ER+/low TILs group), and the 39 patients in the ER+/high TILs group were too few for obtaining reliable results. The risk reduction after PMRT in terms of OS was, nevertheless, similar to that of the 67 patients with ER-/high TILs BC (23% vs. 19% difference in ER– and ER+, respectively) (). Supplemental Figure 2 further shows how the ER–/low TILs group differs from the remaining patients (either high TILs or ER + tumors).
Figure 3. Kaplan–Meier plots for overall survival (OS) for (A,B) estrogen receptor (ER) negative and (C,D) ER-positive tumors divided according to level of tumor-infiltrating lymphocytes (TILs) and stratified according to randomization to post-mastectomy radiotherapy (PMRT) or not (red – PMRT, blue – no PMRT). Actuarial risks at 5, 10 and 20 years and risk difference in actuarial risks at 20 years with 95% confidence intervals are provided, as well as p-values for Log Rank tests and interaction tests between TILs and PMRT (for both adjusted Cox analysis and risk differences).
The association between high TILs and risk of DM after PMRT also appeared strongest among patients with ER– tumors. The group of patients with ER–/high TILs BC showed an 11% improvement from PMRT (60% to 49%) as opposed to a 2% improvement (62% to 60%) for low TILs, but the interaction test was non-significant (p = 0.71) (Supplemental Figure 3(E–H)). The benefit of PMRT on the risk of LRR was not influenced by the level of TILs (Supplemental Figure 3(A–D)).
When attempting to further divide the ER- patients into subtypes according to HER2 status, the positive association between high TILs and PMRT on OS was clearly seen in the ER–/HER2– group (Supplemental Figure 4(A–D)). The number of patients in each group was, nevertheless, very small.
There was no significant interaction between ER status and menopausal status for any of the clinical endpoints, meaning that the postmenopausal, ER– patients (treated as part of the DBCG82bc trial with tamoxifen) did not have a significantly poorer outcome than the other patients, and adjusting for menopausal status (and hence systemic treatment) did not change the results.
Discussion
The present results showed that high TILs in pretreated BC tumor tissue were significantly associated with a lower risk of distant metastasis (DM) and improved OS in MVA. Furthermore, patients with high TILs in the pretreated tumor gained a significantly greater OS benefit from adjuvant PMRT than patients with low TILs; a trend was also seen for a reduction in risk of DM but not for the reduction of LRR. The association appeared especially pronounced among ER– tumors, primarily encompassing tumors of aggressive biology with a tendency for early DM spread.
The observed improved survival for high TILs patients cannot be explained by a better baseline survival, since a similar risk of overall death (23% vs. 26% for low and high TILs, respectively) and risk of DM (63% vs. 62% for low and high TILs, respectively) were observed among non-irradiated patients in the two TILs groups. This pattern was maintained in the group of ER– tumors, where non-irradiated patients also showed a similar prognosis in the two TILs groups. The association between TILs and PMRT may reflect an inherent difference in radio sensitivity related to the biology of the tumor, for which the presence of TILs could be merely a phenotypical feature of the specific biology and not directly related to the radio sensitivity. In this case, a similarly superior local control in high TILs as compared to low TILs patients would be expected after PMRT; but this was not the case. Kovács et al. [Citation9] saw a larger benefit from RT after BCS in terms of risk of IBTR in patients with low TILs in the SweBCT91RT trial, but a significant interaction between RT and TILs could not be proven. In our study, the LRR risk was not associated with TILs levels.
Accordingly, the observed survival gain from PMRT in the high TILs group cannot be explained as a consequence of better local control leading directly to a reduced risk of derived DM. The benefit of RT in reducing BC mortality without a cause-effect relationship between LRR and survival, but due to a systemic effect outside the treatment field (‘abscopal’ effect) has been discussed by Jatoi et al. [Citation40] inspired by results from several clinical trials incl. the initial studies of the DBCG82bc cohort [Citation29,Citation30]. The underlying mechanism behind systemic effects of RT is suspected to involve activation of cytotoxic T-lymphocytes circulating through the body, reaching distant tumor deposits and leading to tumor regression [Citation41]. Besides destroying tumor cells by a non-immunogenic cell death effectuated by direct damage to the DNA and indirect influence by free oxygen radicals, RT also induces immunogenic cell death. This is mediated through RT-induced release of 1) tumor-associated neo-antigens after local tumor destruction, and 2) damaged DNA gaining access to the cytosol through defect nucleic membranes in irradiated cells and thereby acting as powerful damage-associated molecular pattern (DAMP) activating the cGAS/STING pathway [Citation42]. Both mechanisms lead to the priming of tumor-specific, cytotoxic T-lymphocytes in the draining lymph nodes [Citation16,Citation43] that may circulate and reach distant metastatic deposits.
The present results could reflect activation of RT-induced tumor-specific, immune response in tumors with high TILs leading to regression of distant micro-metastases outside the treatment field and subsequent improvement of OS. This effect may be accentuated in ER– tumors with a predilection for early DM. These findings are in line with previous findings in the DBCG82bc cohort [Citation20] but adds valuable information by apparently identifying a group of ER–/high TILs tumors gaining survival benefit from PMRT. Results from further subdivision into ER– (non-luminal) subtypes were limited by the low number of patients in each group. Furthermore, the patients were treated before the introduction of anti-HER2 therapy, and the cohort is not optimal for drawing conclusions on a differential effect of TILs in HER2– vs. HER2+ patients.
The adverse prognostic effect of TILs according to ER status has previously been speculated to be related to resistance to endocrine therapy [Citation5] and tamoxifen has been found to depress immunity by several mechanisms. Tamoxifen has for instance been described to induce a shift from Th1 toTh2 polarization of CD4+ cells impairing the antitumor response [Citation44]; a mechanism described to be independent of the estrogen receptor. Furthermore, tamoxifen may impair the differentiation and maturation of dendritic cells interfering with T-cell proliferation [Citation45]. In this study, tamoxifen was, according to the study protocol, given to all postmenopausal women regardless of ER status. This limits the possibility of evaluating a possible influence of tamoxifen’s immunomodulating effect on the associations between ER status, PMRT and TILs.
From the present evaluation of TILs, it cannot be deducted, if the observed differences in clinical outcome are related to the presence of specific immune cells (e.g., cytotoxic T-cells) or variabilities in cGAS/STING expression. Neither can it be determined, if results are influenced by variation in the composition of immune cells between ER– and ER + tumors. Ongoing studies on the DBCG82bc cohort address these questions.
Several large clinical studies have shown a disease-free survival benefit in patients with extended nodal irradiation [Citation46,Citation47], and an OS benefit with irradiation of the internal mammary nodes (IMN) has been proven in the DBCG-IMN1 cohort [Citation25]. The PMRT in our study was delivered to the chest wall and lymph nodes after removal of the whole mammary gland with residues of tumor tissue likely to be minute. The observed association between TILs and RT may, therefore, be mediated through irradiation of the regional lymph nodes instead of the chest wall. An examination of TILs in the IMN cohort has recently been initiated to further explore this association.
The present results beg the intriguing question of whether ‘cold tumors’ with few TILs can become ‘hot tumors’ and gain the same survival benefits from PMRT. Checkpoint inhibitor antagonists may assist in pushing the balance toward immune-competence, and the possible synergistic effect between RT and checkpoint inhibitors is being extensively studied (reviewed in [Citation48,Citation49]). Immunotherapy reactivates, however, the adaptive immune response and is most effective in patients with an already preexisting immune response including the presence of TILs. ‘Kickstarting’ the immune-response and turning ‘cold tumors’ into ‘hot tumors’ is currently being examined, and e.g., delivery of a low dose RT (8 Gy/3 fractions) in combination with immunotherapy has proven successful in preclinical studies [Citation50].
The cut off of 30% to distinguish ‘cold tumors’ with low TILs vs ‘hot tumors’ with high TILs was chosen because it represented the cut off with the best interobserver agreement, but it was also found to deliver the most optimal associations with clinical endpoints and significant interactions between PMRT and TILs as compared to a 20% or 40% cut off. A similar cut-off for TILs has previously been used by Loi et al. [Citation2].
A limitation to our study is that patients were treated with surgical techniques and systemic treatment not comparable to contemporary treatment, which may compromise the external validity of the size of the effect on BC patients today. Though the absolute survival benefits are likely smaller in currently treated patients due to more aggressive systemic treatment, the biological association between TILs, ER status and PMRT is likely unaltered.
Another limitation is that even though more than 1000 patients were included in the study, only 106 patients harbored a high level of TILs, which led to restrictions in the statistical power in some subgroups due to few patients in each group.
The strengths of the study are the randomized design of the DBCG82bc trial, the long clinical follow-up and a large number of events. This renders the cohort optimal for hypothesis-generating studies as similar recurrence rates are not observed in present days. The TILs evaluation on routinely processed, whole slide HE-sections is further robust and easily applicable in a daily clinical setting. The evaluation is also not affected by age of the blocks as may be the case with gene expression profiling and IHC staining.
In conclusion, BC patients with a high level of TILs in pretreatment tumor tissue gained a significantly larger OS benefit from adjuvant PMRT; a trend was also seen for high TILs and a reduced risk of DM after PMRT. The association was especially strong among ER– tumors. These findings may indicate that PMRT triggers a local immune response inducing a systemic effect outside the treatment field, e.g., by eliminating distant metastatic deposits. Further studies are needed to understand the mechanism behind the association and to explore if patients with ‘cold tumors’ (low TILs) can be turned into ‘hot tumors’ (high TILs) to obtain the same superior survival effect by PMRT.
Supplemental Material
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TT, JA, JO are listed as co-inventors on an application for an international patent number WO2013132354A3, titled ‘Gene signatures associated with the efficacy of post-mastectomy radiotherapy in breast cancer.’
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References
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