Prognostic Value Of Tumor-infiltrating Lymphocytes Research Articles

The Prognostic Value of Tumor-Infiltrating lymphocytes in Stage II Colon Cancer. A Nationwide Population-Based Study

BACKGROUND: Additional prognostic markers are needed for better treatment stratification of stage II colon cancer (CC). We investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in a true population-based cohort of patients with stage II CC. MATERIAL AND METHODS: A total of 573 patients were included. Tumor blocks representing the deepest invasive part of the primary tumor were used for analysis. CD3+ and CD8+ TILs at the invasive front were evaluated by immunohistochemistry on whole tumor sections. The invasive area was manually outlined, and Visiopharm Integrator System software was used for quantification. Data were dichotomized for comparison with clinical data. The prognostic value was investigated in Cox proportional-hazard models for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Low CD3+ or CD8+ TILs were significantly associated with poor RFS and OS (P = .0021 and P ≤ .0009, respectively, log-rank test). In multiple Cox regression analysis, low CD3+ and CD8+ TILs were associated with reduced RFS with hazard ratio (HR) = 1.386 (95% CI 1.039-1.850), P = .026, and HR = 1.394 (95% CI 1.029-1.890), P = .032, respectively, independent of age, T-stage, localization, perforation, and microsatellite instability (MSI). In the subgroups of patients with low CD3+ or CD8+ TILs, there was no difference in survival between patients with MSI and microsatellite-stable tumors, (P = .821 and P = .907, respectively). CONCLUSION: Low CD3+ and CD8+ TILs in the invasive area are both related to inferior prognosis of stage II CC, and we recommend either of these parameters to be considered as additional high-risk factor.

Some aspects of immunotherapy in colon cancer

Colon cancer is known to be resistant to immunotherapy; however, during the last few years, researchers managed to identify a subgroup of patients that response to anti-PD-1 therapy. This encouraged molecular biologists, immunologists, and clinical oncologists to reconsider the role of immunotherapy for colon cancer. A substantial number of studies devoted to this problem have been published so far, which allowed us to prepare a literature review. This review covers the main trends in immunotherapy of colon cancer, including prognostic value of tumor-infiltrating lymphocytes, efficacy of immune checkpoint inhibitors, bispecific monoclonal antibodies, and antitumor vaccines, as well as transformation of non-inflammatory cancer phenotype into the inflammatory one.

Impact of pathological features of brain metastases in prognosis.

To evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and Ki67 in brain metastasis lesions, and the effect of adding them to variables of graded prognostic assessment score. Clinicopathological information from 111 medical charts of brain metastasis patients was obtained, and TIL distribution (n=84), Ki67 index (n=79) and CD3 TIL (n=64) were prospectively evaluated. Most frequent TIL pattern was perivascular (67.8%), and median Ki67 and CD3 TIL percents were 30 and 4.8%, respectively. Ki67≥15 was associated with shorter survival (p=0.018) but CD3 TIL was not (p=0.870). The highest graded prognostic assessment score was not associated with survival (p=0.648), however, those with low Ki67 and high score was associated with better outcome (p=0.007). High Ki67 index in brain metastasis carries a worse prognosis.

Proportion of CD4 and CD8 tumor infiltrating lymphocytes predicts survival in persistent/recurrent laryngeal squamous cell carcinoma

Tumor infiltrating lymphocytes (TILs) have been shown to be an important prognostic factor in patients with previously untreated head and neck cancer. After organ preservation therapy for laryngeal cancer and subsequent persistence/recurrence, the prognostic value of TILs is unknown. Our goal was to determine if TILs have value as a prognostic biomarker in patients with surgically salvageable persistent/recurrent laryngeal squamous cell carcinoma.Levels of TILs were quantified on tissue microarrays from 183 patients undergoing salvage total laryngectomy for persistent/recurrent laryngeal cancer after radiation or chemoradiation between 1997 and 2014. Demographic and clinical data were abstracted. Immunohistology evaluation included CD4, CD8, PDL-1, p16, CD31, Vimentin, EGFR, and p53.Elevated levels of either CD8 or CD4 positive TILs were associated with improved disease specific survival (CD8: HR 0.46, 95% CI 0.24–0.88, CD4: HR 0.43; 95% CI 0.21–0.89) and disease free survival (CD8: HR 0.53, 95% CI 0.29–0.94, CD4: HR 0.52; 95% CI 0.27–0.99). Levels of CD8 (HR 0.74; 95% CI 0.47–1.17) or CD4 (HR 0.66; 95% CI 0.40–1.08) TILs were not significantly associated with overall survival. In bivariate analysis, patients with elevated CD4 and/or CD8 TILs had significantly improved disease specific survival (HR 0.42; 95% CI 0.21–0.83) and disease free survival (HR 0.45; 95% CI 0.24–0.84) compared to patients with low levels of CD4 and CD8. PDL-1, p16, CD31, Vimentin, EGFR, and p53 were not significant prognostic factors. On multivariate analysis, elevated CD8 TILs were associated with improved disease specific survival (HR 0.35; 95% CI 0.14–0.88, p = .02) and disease free survival (HR 0.41; 95% CI 0.17–0.96, p = .04).CD8, and possibly CD4, positive TILs are associated with favorable disease free and disease specific survival for recurrent/persistent laryngeal cancer.

Abundant tumor infiltrating lymphocytes after primary systemic chemotherapy predicts poor prognosis in estrogen receptor-positive/HER2-negative breast cancers.

The therapeutic effect of systemic treatment for breast cancer (BC) generally depends on its intrinsic subtypes. In addition, tumor infiltrating lymphocytes (TILs) are considered to be an independent factor for tumor shrinkage and disease prognosis. High TILs at baseline or after primary systemic chemotherapy are reported to be associated with better survival in triple-negative or human epithelial growth factor receptor 2 (HER2)-positive BCs. However, the prognostic value of TILs in estrogen receptor (ER)-positive and HER2-negative (ER+/HER2-) BC is still controversial. We assessed TIL score (low, intermediate, and high) before and after primary systemic chemotherapy in every subtype of BC, and compared the clinical outcomes. Biopsy specimens of 47 triple-negative, 58 HER2+ and 91 ER+/HER2- BCs were used to assess TILs before treatment. To assess TILs after treatment, we examined residual invasive carcinoma in surgically resected samples of 28 triple-negative, 30 HER2+ and 80 ER+/HER2- BCs. A high TIL score in triple-negative BC before treatment resulted in a significantly higher proportion of pathological complete response (pCR). In contrast, ER+/HER2- BC exhibited fewer instances of pCR than other subtypes. Although not statistically significant, ER+/HER2- cases with a high TIL score also tended to achieve pCR (p=0.088). Moreover, we revealed that low TIL BCs after chemotherapy, but not at baseline, had significantly better relapse-free survival in ER+/HER2- BC (p=0.034). Pathological examination of TILs after treatment may be a surrogate marker for prognosis in ER+/HER2- BC.

Prognostic value of tumour-infiltrating lymphocytes in small HER2-positive breast cancer

BackgroundThe standard treatment for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)–positive breast cancer (BC) is still controversial. Our aim was to assess the prognostic role of tumour-infiltrating lymphocytes (TILs) in patients with stage pT1a–b HER2-positive BC. Patients and methodsHaematoxylin and eosin slides from node-negative, pT1a–b HER2-positive BC surgical specimens were retrieved from pathology archives to assess TILs and their association with outcome. ResultsTILs were evaluated in 205 patients with HER2-positive, pT1a–b tumours, who underwent breast surgery between 1997 and 2009 at the European Institute of Oncology. At a median follow-up of 11 years, we did not observe any association between the presence of TILs, either assessed as a continuous or dichotomous variable (<50 versus ≥ 50%), and outcome. Within the subgroup of patients with pT1a tumours who did not receive any adjuvant therapy (36/97 patients), the rate of disease-free survival events was lower in lymphocyte-predominant BC (LPBC) as compared with non-LPBC patients (p = 0.066). ConclusionsTILs cannot be used as a prognostic biomarker in pT1a–b HER2-positive BC. Additional biomarkers are needed for selecting patients with stage I HER2-positive BC who candidate to adjuvant therapy de-escalation.

The CD4/CD8 ratio of tumor-infiltrating lymphocytes at the tumor-host interface has prognostic value in triple-negative breast cancer

Compelling evidence has demonstrated the prognostic value of tumor-infiltrating lymphocytes (TILs), especially in triple-negative breast cancer (TNBC). However, only a limited number of studies to investigate the importance of the subsets of T cells in TILs have been carried out, less so the significance of the location of these TILs. In this study, we explored in a cohort of 42 consecutive TNBC cases the prognostic significance of TIL subsets at the tumor-host interface (within 1 high-power field [0.5 mm] of the invasive front) and compared them with TILs within the intratumoral stroma. Given the reported importance of TILs in HER2-overexpressing breast cancer, a subset of such tumors was also included for comparison. The range was wide in both locations; nevertheless, the mean CD4+ and CD8+ T cell count was significantly higher at the tumor-host interface than that found within the intratumoral stroma (both P<.0001). The number of CD4+ or CD8+ T cells at either location was not significantly associated with distant relapse-free or overall survival. However, the CD4/CD8 ratio at the tumor-host interface was significantly associated with both relapse-free survival (hazard ratio 0.2, P=.002) and overall survival (hazard ratio 0.13, P=.002), whereas this association was not seen for the CD4/CD8 ratio within the intratumoral stroma. As expected, both tumor size and nodal status were significantly associated with survival outcomes. The findings further support the contention that TILs, as markers of regional immune escape, are of prognostic importance in TNBC progression and that the CD4/CD8 ratio of TILs at the tumor-host interface plays a distinctive role, thus appearing to be of clinical relevance.

Prognostic value of tumor-infiltrating lymphocytes in small HER2-positive breast cancer

Prognostic value of tumor-infiltrating lymphocytes in small HER2-positive breast cancer

Predictive and prognostic impact of tumour-infiltrating lymphocytes in triple-negative breast cancer treated with neoadjuvant chemotherapy.

IntroductionIn locally and locally advanced triple-negative breast cancer (TNBC), neoadjuvant chemotherapy (NAC) only induces a pCR in 30–35% of patients. Clinical and pathological factors are not enough to distinguish the patients who have no chance of a pCR or not. The tumour microenvironment is critical for cancer and tumour-infiltrating lymphocytes (TIL). Moreover, the NAC scenario is the perfect setting to study possible changes in TIL levels.Material and methodsUsing our prospective maintained breast cancer (BC) database, we identified 164 TNBC patients treated with NAC between 1998 and 2015 with enough samples of diagnostic biopsy and after surgery. Evaluation of TILs before and after NAC followed a standardised methodology for visual assessment on haematoxylin–eosin sections and the amounts of TILs were quantitated in deciles. We categorised lymphocyte-predominant breast cancer cutoff according to a receiver operating characteristic (ROC) analysis. We categorised LPBC as involving > 40% lymphocytic infiltration tumour stroma. The primary end point was predictive value of TILs to NAC, and the secondary end point was disease-free survival (DFS). DFS was analysed using the Kaplan–Meier method and the groups were compared with a long-rank test. Univariate and multivariate Cox models were used to generate hazard ratios for determining associations between variables such as TIL after NAC and DFS.ResultsA total of 164 TNBC patients were treated with NAC and surgery. The main patients’ characteristics are listed in Table 1. We identify different pathological complete response to anthracycline and taxane-based NAC; LPBC subgroup 51 from 58 patients (88%) pCR versus non- lymphocyte-predominant breast cancer (LPBC) subgroup 10 from 106 (9%) pCR, p = 0.001. At a median follow-up of 78 months, LPBC was associated with better DFS; the three-year Kaplan–Meier estimates for DFS were 2% and 30 % for patients with LPBC and non-LPBC, respectively, p = 0.01. Univariate and multivariate analysis confirmed TIL to be an independent prognostic marker of DFS.ConclusionsTumour-infiltrating lymphocytes could be routinely used in locally advanced TNBC treated with anthracycline and taxane, such as biomarker, to be enabled the identification of different two subgroups: LPBC patients have a very high response to NAC pCR 88%, meanwhile non-LPBC patients only achieve 9%. Moreover, non-LPBC patients have a worse prognosis than LPBC patients. This data verified the predictive and prognostic value of TIL.

The Prognostic Value of Tumor-infiltrating Lymphocytes in Hepatocellular Carcinoma: a Systematic Review and Meta-analysis

Previous clinical studies have found that the levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in hepatocellular carcinoma (HCC). However, these conclusions and data remain controversial. We performed a systematic review and meta-analysis to assess the prognostic value and clinical utilization of TILs in patients with HCC. A total of 23 relevant studies of 3173 patients were included into our meta-analysis. The results demonstrated that high levels of CD8+ and CD3+ TILs had a better prognostic value on overall survival (OS), with HRs of 0.71 (P = 0.04) and 0.63 (P = 0.03), respectively, compared to low levels, as did high levels of CD8+, CD3+ and CD4+ TILs on disease/recurrence-free survival (DFS/RFS), with HRs of 0.66 (P = 0.01), 0.60 (P = 0.01) and 0.79 (P = 0.04), respectively. In contrast, high levels of FoxP3+ TILs had a worse prognostic value on OS and DFS/RFS, with HRs of 2.06 (P < 0.00001) and 1.77 (P < 0.00001), respectively. The FoxP3+/CD4+ and FoxP3+/CD8+ ratios negatively correlated with OS and DFS/RFS. These findings suggest that TILs may serve as a prognostic biomarker in HCC. However, further research should be performed to clarify the clinical value of TILs in HCC.

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions.

The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as a biomarker in early-stage breast cancer has been established by assessing tumor samples in thousands of patients from large prospective clinical trials of adjuvant therapy. There is a strong linear relationship between increase in TILs and improved disease-free survival for triple-negative and HER2-positive disease. Higher levels of TILs have also been associated with increased rates of pathological complete response to neoadjuvant therapy. TILs have potential clinical utility in breast cancer in a number of areas. These include prediction of responders to immune checkpoint blockade, identification of primary HER2-positive and triple-negative patients who have excellent prognoses and may thus be appropriate for treatment de-escalation, and potentially incorporation into a neoadjuvant endpoint which may be a better surrogate maker for drug development.

A Novel Numerical Scoring System for Melanoma Tumor-infiltrating Lymphocytes Has Better Prognostic Value Than Standard Scoring.

The purpose of this study was to evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) in melanoma and to determine whether a simpler numerical scoring system would be more effective. In total, 655 patients presenting to a UK teaching hospital with primary invasive melanoma were analyzed. TILs were rescored using the standard Clark's method and univariable and multivariable analyses of the effect of TILs on overall survival (OS), disease-specific survival (DSS), and metastasis-free survival (MFS) was assessed using Cox regression. In total, 30 (5%) melanomas showed absent, 464 (71%) nonbrisk, and 161 (24%) brisk TILs. There was a statistically significant relationship between TILs and Breslow thickness, age, melanoma type, mitotic rate, and histologic regression. TIL grade was a significant predictor of MFS in multivariable analysis (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25-0.77) but was not significant for OS or DSS. By contrast, when a simple numerical TIL percentage score was used this was a strong predictor of OS (HR, 0.55; 95% CI, 0.38-0.78), DSS (HR, 0.25; 95% CI, 0.14-0.44), and MFS (HR, 0.32; 95% CI, 0.21-0.51) in multivariable analysis. The percentage TIL score was also significant when adjusted for the prognostic gold standard, American Joint Committee on Cancer stage: OS (HR, 0.66; 95% CI, 0.46-0.95), DSS (HR, 0.33; 95% CI, 0.19-0.60), and MFS (HR, 0.41; 95% CI, 0.26-0.65). The TIL percentage score was subsequently validated in new cases. In summary, this study strongly confirms that higher amounts of TILs are associated with better prognosis and in addition demonstrates the value of a simplified numerical TIL scoring system.

P-269 - Correlation between the prognostic value of tumor-infiltrating lymphocytes (TILS) and sidedness in colorectal cancer (CC) patients (pts)

Introduction: Right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC) have a different biology and genomic pattern. Primary tumor location is emerging as an important prognostic factor in metastatic CC patients eligible to target therapy. In a previous work, we have reported that specific tumor-infiltrating lymphocytes (S-TILs) (CD3+, CD8+, CD45RO+) may represent a valuable prognostic tool to drive the decision making-process in stage II colon cancer (CC) disease. In this study we aim to evaluate the relationship and the prognostic impact between TILs and the anatomical subsite (RCC vs LCRC) in primary non metastatic CC, regardless the stage. Methods: We performed a retrospective analysis on 48 CC pts (17F/31M, median age 68.1 - range 52-91 years) underwent adjuvant therapy, of which 33 relapsed and 15 did not, subdivided according to the anatomical sidedness of their primary tumors. We analyzed, by immunohistochemical staining, the density of CD3+, CD8+ and CD45RO + (memory cells) in the center of the tumor (CT) and in its invasive margin (IM) within the surgical tissues samples after radical surgery, comparing them on their primary tumor location. Measurements were recorded by image analysis as the number of positive cells per tissue surface unit in square millimeters. For each marker, we identified two grading of staining, high density (HD) or low density (LD), where the cut-off was the median value observed. Kaplan-Meier analysis was applied to compare the effect of TILs, between HD and LD, on disease free survival (DFS) and overall survival (OS) in the subgroups pts of RCC and LCRC. Due to the small cohort of 48 pts we have not been able to combine the tumor stage II (N = 15) and III (N = 33) with anatomical sidedness, thus this analysis was conducted subdividing patients in 17 RCC and 31 LCRC. Results: When we stratified pts by TILs density for each specific marker (CD3+, CD8+ and CD45RO+) for the anatomical sidedness, HD TILs pts showed a trend in LCRC for a longer OS compared to RCC pts, which became statistically significant for CD45RO+ in CT (p = 0.0061). On the contrary, for the entire cohort of 48 pts no differences in OS and DFS were found between LCRC and RCC pts without stratification for TILs. DFS was significantly improved in LCRC at both IM and CT only in pts with HD CD3+. On the contrary RCC showed DFS benefit only in HD CD45RO+ at IM. OS was significantly improved in LCRC in pts showing HD CD3+ and CD45RO+ at CT. HD CD45RO+ was also significant at IM. No significant differences were observed among CD3+, CD45RO+, CD8+, HD vs LD, in RCC. Conclusion: Specific HD TILs is an important prognostic factor regardless of sidedness of CC tumour; furthermore, in our analysis, the presence of HD CD45RO+ in CT of LCRC is correlated to a better survival.

Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis.

BackgroundIn patients with gastric cancer, the prognostic value of tumor-infiltrating lymphocytes (TILs) is still controversial. A meta-analysis was performed to evaluate the prognostic value of TILs in gastric cancer.Materials and methodsWe identify studies from PubMed, Embase and the Cochrane Library to assess the prognostic effect of TILs in patients with gastric cancer. Fixed-effects models or random-effects models were used estimate the pooled hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS), which depend on the heterogeneity.ResultsA total of 31 observational studies including 4,185 patients were enrolled. For TILs subsets, the amount of CD8+, FOXP3+, CD3+, CD57+, CD20+, CD45RO+, Granzyme B+ and T-bet+ lymphocytes was significantly associated with improved survival (P < 0.05); moreover, the amount of CD3+ TILs in intra-tumoral compartment (IT) was the most significant prognostic marker (pooled HR = 0.52; 95% CI = 0.43–0.63; P < 0.001). However, CD4+ TILs was not statistically associated with patients’ survival. FOXP3+ TILs showed bidirectional prognostic roles which had positive effect in IT (pooled HR = 1.57; 95% CI = 1.04–2.37; P = 0.033) and negative effect in extra-tumoral compartment (ET) (pooled HR = 0.76; 95% CI = 0.60–0.96; P = 0.022).ConclusionsThis meta-analysis suggests that some TIL subsets could serve as prognostic biomarkers in gastric cancer. High-quality randomized controlled trials are needed to decide if these TILs could serve as targets for immunotherapy in gastric cancer.

Prognostic role of tumor-inflating lymphocytes in gastric cancer: A systematic review and meta-analysis.

e15578 Background: Tumor-infiltrating lymphocytes(TILs) may act as major determinants of the host immune response to tumor cells. However, the potential prognostic value of TILs in gastric cancer remains controversial. This meta-analysis analyzed the associations between TILs and survival outcomes in gastric cancer. Methods: Eligible 24 published studies were identified by searching the PubMed and Google scholar databases. The primary clinical outcome was defined as overall survival (OS) or disease-free survival (DFS), which were analyzed by subgroups such as TILs subtype. The total of the study sample sizes in eligible 24 published studies was 3,229, which ranged from 52 to 273 (median, 120) patients. All studies were non-randomized and retrospective study. The only multivariate hazard ratio(HR) among patient survival data were pooled, and pooled multivariate HR with 95% confidence intervals (95% CI) were used to calculate the strength of this association between TILs expression and survival outcome. Results: The pooled multivariate hazard ratios suggested that high expression of TILs was associated with better overall survival outcome (pooled HR = 0.69, 95% CI 0.57–0.82), compared to low TILs expression in twenty-three eligible studies, particularly in CD8(+) lymphocytes (pooled HR = 0.63, 95% CI 0.48 –0.83). In contrast, a pooled analysis of the FOXP3 (+) T cells or Treg subgroup showed that high FOXP3 (+) expression was negatively correlated with OS (pooled HR = 1.88, 95% CI 1.34 –2.63). In an analysis of seven studies on DFS, the infiltration by TILs, CD4(+) or CD8(+) lymphocytes (pooled HR = 0.59, 95% CI 0.42 –0.81), not by the infiltration of FOXP3 (+) T lymphocytes (pooled HR = 1.82, 95% CI 1.30 – 2.53), was significantly associated with better survival outcome. Conclusions: The results from this meta-analysis suggest that TILs and TILs subsets expression can be a potential prognostic biomarker in patients with gastric cancer. Key Words: Tumor-infiltrating lymphocytes, gastric cancer, prognosis, meta-analysis

Rituximab treatment circumvents the prognostic impact of tumor-infiltrating T-cells in follicular lymphoma patients

Previous immunohistochemical (IHC) studies showed controversial data about the prognostic value of tumor-infiltrating lymphocytes (TILs) in follicular lymphoma (FL). To clarify this issue, a large series of FL samples from rituximab-treated patients enrolled in the randomized PRIMA trial was examined. IHC was quantified using automated image analysis in 417, 287, 418, 406, 379, and 369 patients for CD3, CD4, CD8, PD1, ICOS, and FOXP3, respectively. RNAseq analysis was used to quantify TIL-related mRNA transcripts from 148 patients. When each IHC marker was used as a continuous variable in the whole cohort, high CD3 counts were associated with better progression-free survival (PFS) (P = .025). When an optimal IHC cut point was applied to the whole patient population, high CD3 counts and high PD1 counts were associated with better PFS (P = .011 and P = .044, respectively), whereas none of the other TIL markers had any significant correlation with outcome. When a stringent analysis was performed by dividing the whole cohort into a training set and a validation set, none of the TIL markers showed a prognostic significance in both groups. RNAseq analysis showed a significant correlation between high levels of CD3 and CD8 transcripts and better PFS (P = .001 and P = .037, respectively). No prognostic correlation was found as to the level of other immune gene transcripts. These results suggest that the IHC prognostic value of TILs is circumvented by rituximab treatment, although there is a trend for high numbers of CD3+ TILs to correlate with better PFS.

Abstract S1-08: Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study

Abstract Background The presence of stromal TILs (sTILs) is associated with a better prognosis with anti-HER2 therapy in primary HER2-positive BC. The prognostic value of TILs in the advanced setting with pertuzumab-based therapy is unknown. Methods The CLEOPATRA trial randomly assigned 808 patients with metastatic HER2-positive BC to receive pertuzumab or placebo in combination with trastuzumab and docetaxel. We evaluated %TILs using our previously described method. For concordance evaluation, 40 slides from metastatic samples were independently analysed by two pathologists. TILs were examined for associations with clinicopathological factors, progression-free survival (PFS), overall survival (OS), and treatment interactions using Cox regression models fitting sTILs as a continuous variable (per 10%) adjusting for treatment arm, age, estrogen receptor (ER) status, PIK3CA genotype, and visceral vs. non-visceral disease at screening. Results Tumour samples from 678 (84%) participants were available. 519 (76.5%) were archival and 155 (22.9%) were obtained fresh, ≤45 days prior to study treatment start. Median follow-up for OS was 50 months, with 519 PFS events and 358 deaths. 54% of patients were treatment naïve i.e. had not received prior chemotherapy nor trastuzumab. The median sTIL level was 10% (1-95%). sTIL evaluation was highly concordant between pathologists (R=0.93). Fresh vs. archival samples had significantly lower sTILs (10% vs 15%, p=0.0004). sTIL levels significantly differed by ethnicity (15% Asians, 10% white, 5% African-Americans, p=0.0007), but not age (p=0.26). Higher sTILs were observed in ER-negative vs. ER-positive tumors (15% vs 10%, p&amp;lt;0.001). In the whole cohort for PFS, higher sTIL levels trended towards a better outcome independent of treatment (adjusted HR:0.95, 95%CI:0.90-1.00, p=0.06). For OS, the prognostic effect of sTILs reached statistical significance, with each 10% increase in sTILs associated with an 11% reduction in the risk of death (adjusted HR:0.89, 95%CI:0.83-0.96, p=0.001). The prognostic effect was observed independent of treatment arm, ER status, PIK3CA genotype, prior treatment or presence of visceral disease at screening, and in both fresh and archival tissue samples. There was no significant interaction (int) between pertuzumab and sTILs for PFS (Pint=0.4) nor OS (Pint=0.6). There were no significant interactions between pertuzumab and sTILs for OS in subgroups of PIK3CA mutated (Pint=0.2) or PIK3CA WT (Pin=0.2), nor treatment naive (Pint=0.3) vs prior treatment (Pint=0.5). The 5-year estimates of OS according to median ≤10% vs &amp;gt;10% sTILs in the placebo arm were 26% (95%CI:19-37) vs. 39% (95%CI:32-48), while in the pertuzumab arm 42% (95%CI:33-53) vs. 56% (95%CI:47-66) respectively. Conclusion In advanced HER2-positive disease, sTILs are still evident, though at lower levels, but are nevertheless significantly associated with prognosis, with effects stronger for OS than PFS. This suggests that the influence of anti-tumour immunity persists in the advanced first line setting and that enhancement by immunotherapeutic approaches could potentially further improve survival. Citation Format: Luen S, Salgado R, Stephen F, Peter S, Jennifer E-W, Emma C, Astrid K, Sandra SM, Jose B, Stefan M, Sherene L. Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-08.

The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer.

The prognostic value of tumor-infiltrating lymphocytes (TILs) in ovarian cancer is still in controversial. This study is aimed to assess the impact of different TIL subsets on the progression free survival (PFS)/disease free survival (DSS) and overall survival (OS)/disease specific survival (DSS) in ovarian cancer. A comprehensive literature search in PubMed, ISI Web of Science, and Medline was performed to identify relevant studies evaluating the prognostic value of TILs in ovarian cancer. Reviews of each study were conducted and data were extracted. The main outcomes analyzed were PFS/DFS and OS/DSS. A total of 21 eligible studies enrolling 2903 ovarian cancer patients were included for the meta-analysis. The overall analysis revealed that intraepithelial CD3+ and CD8+ TILs were strongly associated with improved PFS/DFS (HR=0.53, for CD3+ TILs; and HR=0.50, for CD8+ TILs). Intraepithelial CD8+/Foxp3+ ratios appeared to be associated with improved PFS, though without reaching statistical significance (HR=0.73). Moreover, intraepithelial CD3+, CD8+, and CD103+ TILs were clearly associated with increased OS/DSS (HR=0.50, for CD3+ TILs; HR=0.62, for CD8+ TILs; HR=0.54, for CD103+ TILs). However, intraepithelial FoxP3+ TILs, CD8+/FoxP3+ ratios, CD8+/CD4+ ratios, and stromal TILs had no impact on the OS/DSS (HR=0.98, for FoxP3+ TILs; HR=0.69, for CD8+/FoxP3+ ratios; HR=0.48, for CD8+/CD4+ ratios; HR=0.82, for stromal TILs). In conclusion, the present meta-analysis supports the hypothesis that intraepithelial TILs are predictive biomarkers for the prognosis of ovarian cancer patients. Future randomized studies are needed to verify these observations.

Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple-negative but not estrogen receptor–positive breast cancers

Correlation between tumor-infiltrating lymphocytes (TILs) and complete pathological response (pCR) in breast cancers in neoadjuvant settings have been reported. In this study, we analyzed the association between TILs and diagnostic and prognostic parameters in estrogen receptor-positive (ER+) and triple-negative breast cancer (TNBC) without neoadjuvant treatments. Three hundred forty-four (344) patients who underwent mastectomy for breast cancer (187 ER+ and 157 TNBC) without neoadjuvant treatments were evaluated. Percentage of overall and peripheral TILs were correlated with lymphovascular invasion (LVI), Nottingham histologic grade (NHG, 1/2 versus 3), stage, lymph node status (LN), overall survival (OS), and disease-free survival (DFS). In TNBC, both peripheral and overall TILs were significantly associated with NHG 3 (P<.0001). Peripheral but not overall TILs were significantly associated with better OS (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.91-1.00; P=.0354) and DFS (HR: 0.95; 95% CI: 0.91-1.00; P=.0314) in univariate and multivariate analysis. In ER+ breast cancer, only peripheral TILs were associated with NHG 3 (P=.018) but not with OS or DFS (both P>.05). In ER+ breast cancer, there was a negative association between Oncotype DX recurrence score and both overall (P=.0007) and peripheral TILs (P=.0119). In conclusion, peripheral but not overall TILs correlate with better OS and DFS in TNBC, indicating the location of TILs may be important in TNBC. The negative association between TILs and Oncotype DX score in ER+ may indicate the possible prognostic value of TILs in ER+ breast cancer.

Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients With Head and Neck Squamous Cell Carcinoma

BACKGROUND: The prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) remains controversial. Additionally, there is no standardized approach or cutoff value for evaluating TIL levels. The aim of this study was to establish a feasible method and criterion to assess TIL levels for future clinical practice and research use and to explore the relationship between TIL levels and prognosis. PATIENTS AND METHODS: This retrospective cohort study reviewed the records and pathological sections of 202 patients with HNSCC who were surgically treated at Beijing Stomatological Hospital, Capital Medical University, from January 1998 to January 2011. The predictor variable was the TIL level. The main outcome assessment parameters were disease-free survival (DFS) and disease-specific survival (DSS). RESULT: The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level. A cutoff value equal to 70% could be taken as a threshold for TIL assessment, with a TIL level higher than 70% associated with a better prognosis (DFS rate: 51.9%, P = .018; DSS rate: 59.3%, P = .049). The Cox regression model showed that the TIL level was an independent prognostic factor for DFS (hazard ratio (HR): 0.786, 95% CI: 0.618-0.999, P = .049). CONCLUSION: The TIL level is closely related to the prognosis of patients with HNSCC. A threshold value of 70% is appropriate for TIL assessment, as patients with a TIL level higher than 70% show a better prognosis. Thus, the TIL level might serve as an independent predictor for HNSCC recurrence.