Recent Advancements in Immunotherapy for the Treatment of Metastatic Breast Cancer.

Introduction High levels of TIL at baseline are associated with higher pCR rates and better overall survival in TNBC. Recent studies have also indicated that higher TIL in post-NACT residual disease in TNBC are an important independent predictor of improved survival. We evaluated the role of mid-treatment (post-AC; Adriamycin/Cyclophosphamide) TIL in predicting pCR rates in early-stage TNBC. Methods Of 242 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443), 156 patients had pre-AC TIL and pCR status available for this analysis. Both pre-and post-AC TIL counts were available in 29 patients. Post-AC TIL counts for the remaining patients were imputed using linear regression with age, race, stage III, vimentin >50% and post-AC tumor volume reduction. Using these imputed TIL counts we evaluated the association of post-AC TIL with pCR. We also evaluated the change in TIL before and after treatment with AC. Results At baseline the median TIL count was 10% (n=156). In the post-AC samples, the median TIL count was 5%. Using imputed TIL counts, we did not conclude that post-AC TIL was associated with pCR (p= 0.28). Using a cut-point of 15% TIL, our analysis showed that baseline TIL is more strongly correlated with pCR than post-AC TIL (Table 1). In our univariable logistic regression, both baseline TIL and the difference in TIL pre-and post- treatment were significantly associated with pCR (p= 0.0015 and p=0.0068, respectively), however in the multivariable analysis only baseline TIL was significant. Our analysis did show that a decrease in TIL from pre- to post-treatment was significantly associated with pCR (p=0.022). However, this measure was not significant in our logistic regression model when pre-TIL was also included. Conclusion Higher pre-treatment TIL correlated more strongly with pCR rate when compared to post-AC TIL. Pre-treatment high TIL was associated with pCR regardless of changes in TIL pre and post treatment. Table 1. Changes in TIL before and after treatmentBaseline TILPost-AC TILN#pCR (%)LowLow6217 (27%)LowHigh4012 (30%)HighLow2513 (52%)HighHigh2916 (55%)TIL; Low: <15, High >15 Citation Format: Nour Abuhadra, Kenneth Hess, Jennifer Litton, Gaiane Rauch, Alastair Thompson, Bora Lim, Beatriz Adrada, Elizabeth Mittendorf, Senthil Damodaran, Rosalind Candelaria, Banu Arun, Wei Tse Yang, Naoto Ueno, Lumarie Santiago, Rashmi Murthy, Nuhad Ibrahim, Sahin Aysegul, William Symmans, Lei Huo, Stacy Moulder. Serial TILs: Evaluating the role of mid-treatment tumor infiltrating lymphocytes (TIL) in predicting pathologic complete response (pCR) in early-stage triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-20.

Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy

Tumor-infiltrating lymphocytes (TILs) are gaining recognition as an important immunological biomarker with therapeutic potential in breast cancer. In this cohort study conducted on patients with advanced breast cancer treated with primary systemic therapy (PST), the TILs concentration was correlated with response to PST and survival outcomes. Patients with primary breast cancer treated with PST between 2016 and 2020 were included in this study, approved by IEC, and registered on ClinicalTrials.gov (NCT05250336). Tumor core biopsies obtained prior to starting treatment from 489 patients were assessed for the proportion of stromal TILs by standardized method and categorized into low (0-10% immune cells), intermediate (11-59%), and high (≥ 60%) TILs. TIL concentration and complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) were correlated. Of the 489 patients, 372 matched the eligibility criteria for assessment of TILs and made the final study cohort. Among these, 135 were luminal, 129 HER2-enriched, and 108 triple-negative breast cancers (TNBC). Proportions of patients with high TILs were greater in TNBC (15.7%) and HER2-enriched (9.3%), compared to luminal cancers (4.4%). High TIL concentration was correlated with higher pCR in all subtypes. A pCR was achieved in 33.3, 50, and 52.9% of high TIL patients in luminal, HER2-enriched, and TNBC subtypes, respectively (p < 0.05). High TILs were linked to longer DFS and OS in TNBC and HER2-enriched breast cancers. In this first study of its kind from a low- and middle-income country, high TILs concentration was found to be a predictor of response to PST across all breast cancer subtypes. TILs concentration was found predictive of better DFS and OS in TNBC and HER2-enriched cancers. Prognostic role of TILs in luminal cancers was not so apparent.

Background: There is a strong evidence indicating that locoregional control of early-stage breast cancer either by lumpectomy with radiation therapy or by mastectomy yields similar rates of disease-free survival (DFS) and overall survival (OS). Recent retrospective review of a Danish prospective database demonstrated a strong favorable interaction between radiotherapy (RT) and all breast cancer subtypes that contain high amount of tumor infiltrating lymphocytes (TILs). Objective: We aim to compare the DFS and OS rates in patients with early-stage triple negative breast cancer (TNBC), whose tumors demonstrate high involvement by TILs after locoregional management by either mastectomy or lumpectomy and whole breast radiotherapy. Methods: We retrospectively reviewed the charts and histopathology slides of patients with TNBC with the clinical stage of T1-T2 N0 who were treated in our center between January 2009 and December 2018. Locoregional management included either mastectomy (no radiation group) or lumpectomy with whole breast irradiation (radiation group). Stromal TILs were estimated by 3 pathologists independently using hematoxylin-eosin staining, following the recommendations of the TILs working group 2014. A competing risk model, Kaplan-Meier analysis and multivariate Cox regression analysis were used to analyze correlations between TILs and clinical outcome. Results: A total of 101 charts were reviewed and 91 were included in the final analysis. Patients were dichotomized into groups of “low TILs” and “high TILs” using a 40% cut off. Approximately 26% of patients (24/91) were “high TILs”. About 46% of the “high TILs” group and 52% of “low TILs” group received RT. In patients with high TILs, 82% received chemotherapy in the "radiation group" and 100% in "no radiation group". In the patients with low TILs, 77% received chemotherapy in the "RT group" and 75% in "no RT group”. Table 1 and 2 depict the 5-year DFS and 5-year OS in "high TILs" and "low TILs" groups in relation to RT, respectively. Conclusion: Our data indicate that in a selected group of high TILs TNBC, RT is associated with significant improvement of 5-year DFS and OS. This improvement is unlikely to be due to improved locoregional control as local failure was rare in all patient groups. This study is limited by its retrospective nature and the low number of subjects. Despite that, our results are important and deserve further confirmation using larger prospective clinical trials. Table 1. 5-year DFS5-year DFSHigh TILsLow TILsRT group100%83.9%No RT group47.1%79.3%p-value0.010.96 Table 2. 5-year OS5-year OSHigh TILsLow TILsRT group100%83.7%No RT group65.6%76.7%p-value0.050.98 Citation Format: Jason Aboudi Mouabbi, Momal Chand, Ramen Sakhi, Daniel Ockner, Susan Szpunar, Carrie L Dul, Tarik Hadid, Zyad Kafri, Amr Aref. Improvement of survival with radiation therapy in early stage triple negative breast cancer patients with high level of tumor infiltrating lymphocytes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-09.

SummaryM2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

Historically, breast tumors have been categorized as non-immunogenic in part due to a paucity of tumor infiltrating lymphocytes (TIL) when compared to other histologies. Multiple studies have now demonstrated an endogenous immune response against breast cancer with tumors having TIL present in the tumor and surrounding stroma. The extent of TIL infiltrate is dictated by the subtype of disease being highest in triple negative breast cancer (TNBC) and lowest in hormone receptor positive, HER2 negative (HR+/HER2-) disease. Recent studies have shown that immunotherapy, in the form of immune checkpoint blockade, can be effective in treating breast cancer patients. Specifically, the IMpassion 130 trial, a phase III study that enrolled over 900 patients with metastatic TNBC and randomized them to the immune checkpoint blockade agent atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel, demonstrated benefit to the addition of immunotherapy with respect to progression free survival as well as overall survival; a difference that was greater in patients with PD-L1 positive disease. Based on these data, the combination of atezolizumab plus nab-paclitaxel was approved for use in patients with PD-L1+ metastatic TNBC. More recently, data from a large phase III trial evaluating the use of the immune checkpoint blockade agent pembrolizumab in the neoadjuvant setting for TNBC patients showed a significant improvement in the rates of pathologic complete response. Based in part on these successes, there is significant enthusiasm for using immunotherapy to treat breast cancer patients. It must be recognized however, that a minority of patients respond. Additional work must therefore be done to expand the number of patients with TNBC who respond as well as to identify strategies for successfully employing immunotherapy for HER2+ and HR+ positive breast cancer. Development of these strategies requires understanding of the cancer immunity cycle and how it can be altered to enhance endogenous immune responses to breast cancer as well as improved understanding of the immune aspects of the tumor microenvironment and how standard of care therapies alter that microenvironment. As an example, there is emerging data showing that PARP inhibition leads to cytoplasmic DNA which activates the STING pathway leading to increased expression of release of type 1 interferons, increased MHC expression and antigen presentation and increased infiltration of effector T cells. Ongoing trials are therefore evaluating those agents in combination with immunotherapy. Our lab has shown that PARP inhibition further modifies the tumor microenvironment suggesting additional therapeutic targets. In addition, there is mounting evidence regarding potential mechanisms behind why some subtypes of breast cancer mount a robust immune response while others remain immunologically “cold”. Differences in antigen processing and presentation likely contribute and understanding how HR+ tumors “hide” from immune recognition could contribute to developing strategies to make these tumors susceptible to immunotherapy. Finally, our group has recently published data demonstrating a difference in susceptibility to immune checkpoint blockade based on age suggesting that a patient’s systemic immune status could predict therapeutic response and potentially be manipulated to enhance that response. Citation Format: E Mittendorf. Immunotherapy in breast cancer: enhancing response to checkpoint blockade [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS1-1.

IA24: Setting the stage for immunotherapy in breast cancer: where are we and where are we going in the clinic?

INTRODUCTION: Abundance of tumor infiltrating lymphocytes (TILs) is well known to be associated with achievement of pathologic complete response (pCR) after neoadjuvant chemotherapy and is a surrogate of better survival in triple negative breast cancer (TNBC). However, the association remains unclear in ER-positive/HER2-negative, which is the most common subtype in breast cancer. Further, pathological quantification of TILs is known for its ambiguity. We hypothesized that abundance of TILs, quantified by transcriptomic signatures, in ER-positive/HER2-negative is associated with different biology and is not a surrogate of survival unlike in TNBC. METHODS: A total of 6035 primary breast cancer patients from three cohorts (TCGA, METABRIC, and SCAN-B) with full transcriptome and clinical data were analyzed. Lymphocyte fractionation in the tumor microenvironment of a bulk tumor was estimated from the transcriptome using two different deconvolution tools, CIBERSORTx and xCell. RESULTS: First, the correlation between TIL score measured histologically on TCGA patients and gene expression of CD3D, CD3E, CD3G, CD8A, CD4, and total lymphocytes, and total T-cells measured by xCell or CIBERSORTx were analyzed. Total sum of lymphocytes by xCell correlated the strongest, thus it was adopted as the TIL score. The TIL score strongly correlated with CD3G, CD3E, CD3D, CD8A, and CD4 gene expressions in both TCGA and GSE96058 cohorts (all r &amp;gt; 0.48). Among the infiltrated cells; M1 and M2 macrophages, dendritic cells, mast cells and monocytes were all higher, and microvascular endothelial cells and pericytes were lower in TIL score high tumors in ER-positive/HER2-negative (all p &amp;lt; 0.01) where M2 and mast cells were not in HER2+ and TNBC in both 2 cohorts. Enrichment of immune related gene sets IL2/Stat5 signaling, IL6/Jak/Stat3 signaling, inflammatory response, and Complement were less in high TIL group of ER-positive/HER2-negativethan HER2 and TNBC. In agreement, cytolytic activity was lower in TIL high of ER-positive/HER2-negative compared from TNBC. On the other hand, high TIL group in ER-positive/HER2-negative had significantly higher intratumor heterogeneity, homologous recombination deficiency, mutation burden, and neoantigens, which were not the case in the other subtypes. In agreement, all the cell proliferation-related gene sets; E2F targets, G2M checkpoint, mitotic spindle, Myc targets v1 and v2, were more strongly enriched in high TIL group of ER-positive/HER2-negative compared from HER2+ and TNBC. MKI67 gene expression and Nottingham histological Grade were uniformly elevated with high TIL regardless of subtypes. In three independent neoadjuvant cohorts, we found that pathologic complete response rates of high TIL group. On the other hand, high TIL group did not show any survival benefit compared with low TIL group in ER-positive/HER2-negative, unlike in HER2+ or TNBC. CONCLUSION: High tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer was associated with less immune response and higher genetic alteration and cell proliferation compared to the other subtypes, leading to better response of neoadjuvant chemotherapy, but no benefit in survival outcome. Citation Format: Rongrong Wu, Masayuki Nagahashi, Masanori Oshi, Yasuo Miyoshi, Takashi Ishikawa, Kazuaki Takabe. Abundance of tumor-infiltrating lymphocytes is associated with pathologic complete response to neoadjuvant chemotherapy but not with survival in ER-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-12.

Introduction: TILs are promising, inexpensive biomarker with prognostic and predictive potential in triple-negative breast cancer. There is no consensus on the appropriate cutoff point to define high and low TILs. Therefore, we aimed to evaluate the prognostic value of TILs in an independent TNBC cohort and to determine an appropriate cut-off point by which to stratify TILs scores into prognostically significant categories. Methods: The study included information on 140 patients with I-III stage TNBC and estrogen receptors &amp;lt;10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller—Payne, and RCB classifications. According to the criteria of the International Working Group, the classification of TILs into low (&amp;lt; 10%), intermediate (≥ 10% to ≤ 40%), and high (&amp;gt; 40%) levels was performed. When analyzing TILs in the main subgroups, we used a binary division of TILs into high level (TILs &amp;gt; 40%) and low (TILs ≤ 40%). The differences between groups were assessed using the Сhi-square test. The correlation was analyzed with Spearman correlation test. Event-free survival (EFS) was estimated by the Kaplan-Meier method and Cox regression analysis. Results: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (&amp;lt;10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (&amp;gt;40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (&amp;gt;40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. When assessing EFS depending on the level of TILs across three cohorts, the 3-year rates were 64%, 65%, and 95% for low, intermediate, and high levels of TILs respectively. No significant differences in EFS were found between the low and intermediate levels of TILs (HR=0.386, 95% 0.10- 1.44, p=0.156). Using the two-tiered system, 3-year EFS in patients with high TILs levels was 95% versus 65% in the low TILs group (HR=0.119, 95% 0.02 - 0.88, p=0.037). Conclusion: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS. Citation Format: Petr Krivorotko, Sheyda Abdullaeva, Tatiana Semiglazova, Anna Artemyeva, Asel Kudaybergenova, Valentina Zagoruiko, Tatiana Kudriashova, Olga Ponasenko, Vladislav Semiglazov, Vladimir Semiglazov. The optimal cut-off point for Tumor-Infiltrating Lymphocytes (TILs) in Triple-Negative Breast Cancer (TNBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-06-26.

Simple SummaryInflammatory breast cancers (IBC) are very aggressive especially the triple negative ones, highlighting the importance of prognostic and predictive factors determination. The evaluation of tumor infiltrating lymphocytes (TIL) is advised in breast cancers but little is known in inflammatory breast cancers, especially the TIL variation, before and after neoadjuvant chemotherapy (NAC). We reported a series of 31 triple negative IBC treated with dose-dense dose-intense NAC and investigated post NAC TIL and TILs variation. We showed that pre-NAC immune infiltration was lower than in the non-inflammatory breast cancer and that TIL increase after NAC is associated with a decrease in EFS. These results suggest that patients whose tumors have TIL enrichment after NAC are at high risk of relapse and could be candidates for adjuvant treatment after NAC.Inflammatory breast cancers are very aggressive, and among them, triple negative breast cancer (TNBC) has the worst prognosis. While many studies have investigated the association between tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) and outcome in TNBC, the impact of post-NAC TIL and TIL variation in triple negative inflammatory breast cancer (TNIBC) outcome is unknown. Between January 2010 to December 2018, all patients with TNIBC seen at the breast disease unit (Saint-Louis Hospital) were treated with dose-dense dose-intense NAC. The main objective of the study was to determine factors associated with event-free survival (EFS), particularly pathological complete response (pCR), pre- and post-NAC TIL, delta TIL and post-NAC lymphovascular invasion (LVI). After univariate analysis, post-NAC LVI (HR 2.06; CI 1.13–3.74; p = 0.02), high post-NAC TIL (HR 1.81; CI 1.07–3.06; p = 0.03) and positive delta TIL (HR 2.20; CI 1.36–3.52; p = 0.001) were significantly associated with impaired EFS. After multivariate analysis, only a positive TIL variation remained negatively associated with EFS (HR 1.88; CI 1.05–3.35; p = 0.01). TNIBC patients treated with intensive NAC who present TIL enrichment after NAC have a high risk of relapse, which could be used as a prognostic marker in TNIBC and could help to choose adjuvant post-NAC treatment.

Background:Tumor-infiltrating lymphocytes (TILs), one of immunological biomarkers have been investigated in breast cancer and other cancers. High levels of TILs or lymphocyte-predominant breast cancer subgroup (LPBC) were associated with better prognosis in HER2 positive and triple negative breast cancers from various studies. Recently, TILs is also the predictive biomarker for response to neoadjuvant chemotherapy. Clinical utility of TILs has been recommended in routine clinical practice for breast cancer patients. However, limitation of TILs in HER2 positive women in Thai ethnicity was reported. So, the aim of this study was to evaluate TILs in combination with clinical values as the prognostic value for predicting the recurrent breast cancer in Thai population. Methods: Four hundred and eighty-six patients with early stage HER-2 positive breast cancer who were diagnosed and treated at King Chulalongkorn Memorial Hospital from January 2005 to December 2016 were reviewed retrospectively. Clinico-pathological features, stromal TILs classified as low, intermediate and high, and survival outcomes were analyzed. Results: The median age was 52 years (26-85). Of the 486 HER2 positive women, 56% had postmenopause, 54.5% had T2 tumor, 47.7% had node negative, 66.8% had stage I-II, 44.6% had lymphovascular invasion, and 47.5% had positive hormonal receptor. For the primary treatment, 67.3% underwent modified radical mastectomy, 96.5% received neoadjuvant/adjuvant chemotherapy, 69.7% received adjuvant trastuzumab, 46.7% received adjuvant hormonal therapy. In 92 recurrent patients (18.9%), distant metastasis was identified in 67.4%. In 100 available tissues for evaluating stromal TILs, only 14 (14%) had high stromal TILs (at least 50%) and 46 patients (46%) had recurrent disease. Twenty three of 39 (59%)in low stromal TILs group had disease recurrence while only 4 out of 14 (28.6%) in high stromal TILs had recurrent disease. Median percentage of stromal TILs in recurrent and non-recurrent group was 17.5% and 27.5%, respectively. From multivariate analysis, high stromal TILs (HR 0.52 [95%CI 0.32-0.85]; p = 0.01) and trastuzumab used (HR 0.39 [95%CI 0.25-0.61]; p &amp;lt;0.001) were associated with decreased risk of recurrences. After median follow up of 4.1 years, 5-years disease free survival (DFS) and 5-years overall survival (OS) were 80.9%, 86.8%, 69% and 92.6%, 91.5%, 94.5% in overall populations, trastuzumab and non-trastuzumab used group, respectively. Additionally, 5-year DFS and 5-year OS were 34.3%, 60.8%, 75.7% and 86.2%, 82.5%, 83.1% in low, intermediate and high stromal TILs subgroup, respectively. Conclusion: High stromal TILs and trastuzumab used were statistically significant prognostic values for predicting disease recurrence in HER-2 positive early breast cancer. Stromal TILs together with clinical values established clinical utility in Thai HER2 positive breast cancer women. Level of Stromal TILs in Overall PatientsStromal TILsTotal (n = 100)No recurrence (n = 54)Recurrence (n = 46)P valueLow (0-15%)39(39%)16(41%)23(59%)0.03Intermediate (20-40%)47(47%)28(59.6%)19(40.4%) LPBC (50-90%)14(14%)10(71.4%)4(28.6%) Citation Format: Prapatsornvichit S, Atikankul T, Sriuranpong V, Poovorawan N, Parinyanitikul N. Prognostic value of tumor-infiltrating lymphocytes (TILs) and clinical values for prediction of breast cancer recurrence in HER2 positive early breast cancer after surgery in King Chulalongkorn Memorial Hospital [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-46.

Background: Triple negative breast cancer (TNBC) is an aggressive subtype that does not express hormone receptors or HER2, and therefore has few targeted treatment options. Tumor-infiltrating lymphocytes (TILs) have become established as promising prognostic markers of host immune response in TNBC. Aim: To elucidate the immune landscape of TNBC to inform future immunotherapeutic strategies and maximize prognostic models in this challenging subtype of breast cancer. Methodology: Using hematoxylin and eosin (H&amp;E) staining, Formalin fixed paraffin embedded (FFPE) tissue slices from 79 patients with histologically confirmed triple negative breast cancer (TNBC) were retrospectively cross-sectionally analyzed. Tumor infiltrating lymphocytes (TILs) were evaluated in the stromal compartment in accordance with the International Immuno-Oncology Biomarker Working Group's standards. TILs were stratified as low (&lt;10%), intermediate (10–49%), and high (≥50%). A total of clinical and pathological data (e.g. tumor size, nodal status, grade and survival) was collected and analyzed with SPSS. Chi square tests were used to examine associations between TIL levels and clinic pathological features and survival analyses were done by Kaplan–Meier and Cox regression methods. Results: We found that 26.6% of TNBC patients had low TILs, 45.6% intermediate, and 27.8% had high TILs out of 79 TNBC patients. Small tumor size (p = 0.018), lower lymph node involvement (p = 0.027), and better tumor grade (p = 0.041) were significantly associated with high TIL levels. The results of Kaplan Meier analysis revealed higher DFS and OS in patients with high TIL (p=0.004 and p=0.011, respectively). High TILs were confirmed as independent predictors for favorable prognosis by multivariate Cox regression. Patients with low TILs were poor prognostic patients. These results suggest that TILs are a useful prognostic factor in TNBC. Conclusion: Lymphocytes infiltrating into the tumor are higher in TNBC patients who have better survival outcomes. TIL assessment provides a useful, easily available prognostic tool for making clinical decisions

Objectives: Tumor-infiltrating lymphocytes (TILs) have been identified as a significant prognostic indicator of response to neoadjuvant therapy and immunotherapy for triple-negative breast cancer (TNBC) patients. Herein, we aim to assess the association between TIL levels and mammographic features in TNBC patients.Methods: Forty-three patients with surgically proven TNBC who underwent preoperative mammography from January 2018 to December 2018 were recruited. Pyradiomics software was used to extract 204 quantitative radiomics features, including morphologic, grayscale, and textural features, from the segmented lesion areas. The correlation between radiological characteristics and TIL levels was evaluated by screening the most statistically significant radiological features using Mann–Whitney U-test and Pearson correlation coefficient. The patients were divided into two groups based on tumor TIL levels: patients with TIL levels <50% and those with TIL levels ≥50%. The correlation between TIL levels and clinicopathological characteristics was assessed using the chi-square test or Fisher's exact test. Mann–Whitney U-test and Pearson correlation coefficient were used to analyze the statistical significance and Pearson correlation coefficient of clinical pathological features, age, and radiological features.Results: Of 43 patients, 32 (74.4%) had low TIL levels and 11 (25.6%) had high TIL levels. The histological grade of the low TIL group was higher than that of the high TIL group (p = 0.043). The high TIL group had a more negative threshold Ki-67 level (<14%) than the low TIL group (p = 0.017). The six most important radiomics features [uniformity, variance, grayscale symbiosis matrix (GLCM) correlation, GLCM autocorrelation, gray level difference matrix (GLDM) low gray level emphasis, and neighborhood gray-tone difference matrix (NGTDM) contrast], representing qualitative mammographic image characteristics, were statistically different (p < 0.05) among the low and high TIL groups. Tumors in the high TIL group had a more non-uniform density and a smoother gradient of the tumor pattern than the low TIL group. The changes in Ki-67, age, epidermal growth factor receptor, radiomic characteristics, and Pearson correlation coefficient were statistically significant (p < 0.05).Conclusion: Mammography features not only distinguish high and low TIL levels in TNBC patients but also can act as imaging biomarkers to enhance diagnosis and the response of patients to neoadjuvant therapies and immunotherapies.

PD-L1 and CD8 are associated with deficient mismatch repair status in triple-negative and HER2-positive breast cancers

A simple and convenient model combining multiparametric MRI and clinical features to predict tumour-infiltrating lymphocytes in breast cancer