The effect of neoadjuvant chemotherapy on tumor-infiltrating lymphocytes in patients with breast cancer.

Aim: This study investigated the effect of neoadjuvant chemotherapy (NAC) on stromal tumor-infiltrating lymphocytes (sTILs) and their treatment response. Materials & methods: 115 patients with pre-NAC core biopsies and post-NAC surgical resection specimens were reviewed. Results: There was no significant change between pre- and post-treatment sTILs. Both pre- and post-NAC sTILs were significantly lower in patients with luminal A subtype. An increase in sTILs was observed in 21 (25.9%) patients after NAC, a decrease in 29 (35.8%) and no change in 31 (38.3%; p = 0.07). Pretreatment sTIL density was independent predictor of pathological complete response in multivariate analyses (odds ratio: 1.025, 95% CI: 1.003-1.047; p = 0.023). Conclusion: High sTIL density in core biopsies was independently related to pathological complete response. In addition, ER appears to be the most crucial factor determining the rate of sTIL.

New studies have shown that the tumor microenvironment is critical in tumor behavior. Immune cells surrounding tumor cells are the main components of the tumor microenvironment. Our study aimed to investigate the change in immune cells before and after chemotherapy in breast cancer patients. Our study included 115 patients. All patients underwent chemotherapy before surgery to shrink the tumor. Tru-cut biopsy pieces and the breast tissue obtained after surgery were examined. The presence of estrogen or progesterone receptors on tumor cells decreased the number of immune cells surrounding the tumor cells. The number of immune cells did not decrease after chemotherapy. Another finding was that the greater the number of immune cells around the tumor, the more likely that the tumor would disappear after chemotherapy.

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer.

BACKGROUND: The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). METHODS: Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs. RESULTS: The median age was 49 (24-76) years. The majority of patients were clinically T3-4 (n = 31, 50.8%) and clinically N1-3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9-70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066-0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12-0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07-0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17-0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15-0.78, p = 0.01) were found to be associated with improved survival. CONCLUSIONS: These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

Clinical impact of PD-L1 expression in triple-negative breast cancer patients with residual tumor burden after neoadjuvant chemotherapy.

BACKGROUND: Studies on PD-L1 expression in breast cancer have gained importance in recent years, especially in triple-negative breast cancer (TNBC). Our aim was to analyze the differential expression of PD-L1 to explore its correlation with response to neoadjuvant chemotherapy (NACT) and patient survival. METHODS: PD-L1 expression was evaluated immunohistochemically (Ventana SP263 clone kit) by staining tumor specimen. PD-L1 positivity was defined as membranous staining > 1%, > 5%, > 10%, and > 20% on either tumor cell (TC) and /or immune cell (IC). RESULTS: Fifty patients with locally advanced TNBC, who had a partial response to NACT, were included in the study. PD-L1 staining was observed in TCs in 25 patients (50%) and in ICs in 23 patients (46%) when PD-L1 > 1% was considered positive. Patients with PD-L1 positivity on ICs were more likely to respond to chemotherapy as measured by "MD Anderson Cancer Center Residual Cancer Burden Index" (14/22, 63.6% vs. 10/27, 37%, p = 0.064). The 5-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 46.3% and 51.4%, respectively. A high (> 20%) tumoral PD-L1 positivity was associated with a better DFS and DSS. CONCLUSIONS: Studies in the literature mostly focused on PD-L1 expression in inflammatory cells. However, our results suggest that patients with a high PD-L1 expression on TCs were more likely to have a better outcome. Since patients with residual tumor burden who express PD-L1 on TILs were more likely to respond to NACT, an immune checkpoint inhibitor therapy in addition to NACT would be an important option for TNBC with locally advanced disease.

Loss of stromal CD73 expression plays a role in pathogenesis of polypoid endometriosis.

PURPOSE: To investigate whether CD73 had a role in the pathogenesis of polypoid endometriosis. METHODS: Our study included 15 cases of polypoid endometriosis, which were diagnosed between 2005 and 2019. Clinical findings were gathered from archive files of relevant clinics and pathology reports. All glass slides were re-examined for confirmation of the diagnosis and the detection of additional microscopic findings. An immunohistochemical examination was performed using anti CD73 antibodies in 15 cases of polypoid endometriosis, and also in a control group that contained 9 cases of endometrial polyps and 9 cases of ovarian conventional endometriosis. RESULTS: In addition to standard gynecologic operations, major non-gynecologic procedures had to be performed in 7 cases. In two cases, the surgical team comprised only general surgeons, and a misdiagnosis of carcinoma was made during the frozen section in one case. The majority of the cases displayed gross polypoid lesions that measured 0.7-13 cm. The most common sites were the ovary and rectosigmoid colon. Microscopically, all lesions exhibited a fibrovascular stroma reminiscent of endometrial stroma, whereas glandular features varied. Immunohistochemical examinations revealed a significant loss of CD73 expression in the stroma of polypoid endometriosis in contrast to the control cases, which retained stromal CD73 expression (p < 0.0001). CONCLUSION: Both pathologists and surgeons performing abdominal surgeries should be aware of polypoid endometriosis because it mimics malignancy with its clinical, gross, and microscopic features. We also conclude that loss of stromal CD73 expression, due to its effect on the extracellular ATP/adenosine balance, may contribute to the pathogenesis of this rare form of endometriosis.

Clinicopathological analysis of borderline ovarian tumours and risk factors related to recurrence: experience of single institution.

This study was conducted to determine the demographic and clinicopathologic characteristics and evaluate the prognostic value of various factors, such as the extensiveness of surgery, related to the tumour itself and the clinical features in the recurrence of borderline ovarian tumours (BOT). We retrospectively evaluated the data of 103 patients with a borderline ovarian tumours treated at our institution between the years 2000 and 2012. The median age was 37 (16-79) years and the majority of the patients were premenopausal (76.7%). During the follow-up, 16 recurrences were observed (15.5%). The multivariate analysis showed that the micropapillary architecture and fertility sparing surgery were the only significant independent predictors for the development of a recurrence amongst all of the demographic and clinicopathological features. In our study group, we identified that the micropapillary architecture itself and the fertility sparing surgery had a significant impact on the development of a BOT recurrence. The patients who possess these features should be followed up more closely for a long time period. Impact statement What is already known on this subject? A borderline ovarian tumour is known as a recurrent disease. The recurrence rate varies between 5 and 20%. It is well known in the literature that patients treated by an oophorectomy have a relatively lower risk of development of a recurrence compared to the patients treated by cystectomy. What do the results of this study add? Although some of the clinicopathological features are shown to be risk factors for the development of a recurrence in many studies, some of the pathological-clinical and the demographic features have not been described as yet, or have been considered to be equivocal regarding the development of a recurrence. In this study, we investigate all possible demographic, pathological, and clinical factors associated with a recurrence. Not only the well-known pathological characteristics but also the new pathological parameters and clinical approaches have been investigated. For instance, microinvasion architecture and lymphadenectomy speculated in the literature as the risk factors for the development of a recurrence, have not been identified as risk factors in our study. On the other hand, our statistical analyses have revealed that micropapillary architecture should be described as a risk factor for the development of a recurrence. What are the implications of these findings for clinical practice and/or further research? We hope our study becomes influential in the literature on the field of a micropapillary architecture and the development of a recurrence. The patients carrying this feature have to be followed up very closely and carefully. Furthermore, our findings have indicated no significant relation between the performing of a lymphadenectomy and the rate of a recurrence. This result might be encouraging for the gynaecological surgeons to refrain from a lymphadenectomy for the borderline ovarian tumours.

Comparison of Pathological Prognostic Stage and Anatomic Stage Groups According to the Updated Version of the American Joint Committee on Cancer (AJCC) Breast Cancer Staging 8th Edition.

BACKGROUND We compared pathological prognostic stage (PPS) with anatomic stage (AS) groups according to the updated version of breast cancer staging of the American Joint Committee on Cancer (AJCC) 8th Edition. MATERIAL AND METHODS We evaluated 353 breast cancer patients initially treated with surgery. AS and PPS were performed by evaluating the pathological data of the patients according to the AJCC 8th Edition breast cancer updated version. Stages and survival rates between the 2 staging systems were evaluated and compared. Disease-free survival (DFS) and disease-specific survival (DSS) were calculated according to both staging systems using Kaplan-Meier test. After the PPS change was made in each AS group, 10-year DFS and 10-year DSS of the changed groups were compared using the chi-square test. RESULTS The median follow-up was 114 months and the median age was 48 years. In 192 (54.4%) patients the stage change. The most significant change was 1-level downstaging in 70 (22.4%) patients, and 2-levels downstaging in 78 (22.1%) patients. Five-year DFS, 10-year DFS, 5-year DSS rate, and 10-year DSS were 86.3%, 80.3%, 93.8%, and 84.1%, respectively. The PPS system was found to provide better prognostic information when the patients with AS IIB and IIIA groups were compared according to the PPS. CONCLUSIONS According to the updated version of the AJCC 8th Edition, half of our patients had stage change when they were evaluated according to AS and PPS system. PPS gives better information about prognosis than does AS.

Loss of ARID1A expression is associated with poor prognosis in invasive micropapillary carcinomas of the breast: A clinicopathologic and immunohistochemical study with long-term survival analysis.

Invasive micropapillary carcinoma (IMPC) of the breast is a highly aggressive and a rare subtype of breast cancer. In this study, we aimed to investigate differences between pure and mixed IMPCs of the breast in terms of clinicopathologic features, and also to analyze the significance of expressions of ARID1A and bcl-2 regarding prognosis. Sixty-nine of IMPCs consisting of 21 pure and 48 mixed type diagnosed at Pathology Department of Istanbul Medical Faculty between 2000 and 2011, who had complete follow-up data, were collected to analyze ARID1A and bcl-2 expressions immunohistochemically with prognosis. The median follow-up period was 94 months. No significant difference was found between pure and mixed type IMPC, as well as in luminal subgroups in terms of prognostic and clinicopatologic features. ARID1A and human epidermal growth factor receptor-2 (Her-2) status were found to be independent prognostic factors of both overall survival (OS) (HR=6.1, 95% CI 1.4-26.6, P=.02; HR=15.9, 95% CI 3.5-71.5, P<.0001, respectively) and disease free survival (DFS) (HR=4, 95% CI 1.1-14.9, P=.04; HR=7.2, 95% CI 2-25.4, P=.002, respectively) in multivariate analysis using Cox regression. The loss of ARID1A expression was significantly related with 10 year-OS (P=.001) and 10 year-DFS (P=.05). Statistically significant effect of ARID1A expression was also stated on DFS and OS in Luminal B group (P=.05 and P=.001 respectively). Pure and mixed type IMPCs are similar in terms of clinicopathologic and prognostic features. The loss of ARID1A expression and Her-2 positivity have significant adverse effect clinical outcomes of IMPC patients.

Role of diffusion-weighted MRI in the differential diagnosis of endometrioid and non-endometrioid cancer of the uterus.

Background Many publications have examined the relationship between apparent diffusion coefficient (ADC) values and tumor grade in endometrial cancer. Nevertheless, none were designed to evaluate according to the histopathological type of endometrioid and non-endometrioid tumors. Purpose To evaluate the role of diffusion-weighted imaging (DWI) in the differential diagnosis of endometrioid and non-endometrioid cancer of the uterus, by comparing them with contrast-enhanced magnetic resonance imaging (MRI) findings. Material and Methods Institutional review board approval and informed consent were obtained. The MRI findings of 63 patients with endometrial cancer were retrospectively evaluated and divided into four groups: Grades I, II, and III endometrioid tumors, and non-endometrioid tumors. ADC values, DWI quotients ( b = 1000 s/mm2), and post-contrast signal intensities between lesions and the myometrium (b1000q-Cq values) were evaluated. The one-way-ANOVA, student's t-test, Kruskal-Wallis test, and receiver operating characteristic (ROC) analysis were used for statistical evaluation. Results Mean ADC values were 0.86 ± 0.14 in Grade I, 0.80 ± 0.7 in Grade II, 0.71 ± 0.14 in Grade III for endometrioid tumors, and 0.70 ± 0.12 in non-endometrioid tumors. There was a significant difference in ADC values between Grade I and Grade III ( P = 0.006), and non-endometrioid tumors ( P = 0.003). The difference was also significant between Grades I + II and Grade III ( P = 0.009), and non-endometrioid tumors ( P = 0.004). Besides, there was a significant difference between endometrioid and non-endometrioid tumors ( P = 0.022). However, when considering b1000q (F = 0.640, P = 0.593) and Cq (χ2 = 6.233; P = 0.101), no significant difference was detected among the groups. Conclusion The difference in ADC values between the endometrioid and non-endometrioid tumors was statistically significant. However, the difference in DWI and contrast-enhancement findings were not statistically significant. Furthermore, the mean ADC values had an inverse relationship with tumor grade in the endometrioid cancer group.

Combination of adjuvant chemotherapy and radiotherapy is associated with improved survival at early stage type II endometrial cancer and carcinosarcoma.

AIMS: The aim of this study was to describe the impact of postoperative adjuvant treatment modalities and identify risk factors associated with recurrence and survival rates in women diagnosed with early stage type II endometrial cancer and carcinosarcoma. METHODS: In this retrospective study, patients diagnosed with early stage (stages I-II) carcinosarcoma and type II endometrial cancer were reviewed. All women underwent comprehensive surgical staging. Postoperative treatment options of chemotherapy (CT), radiotherapy (RT), observation (OBS) and chemotherapy-radiotherapy (CT-RT) combination were compared in terms of recurrence and survival outcome. RESULTS: In CT-RT treatment arm, recurrence rate was found as 12.5% and this result is significantly lower than the other treatment approaches (P = 0.01 CT alone: 33.3%, RT alone: 26.7%, OBS: 62.5%). Three-year disease free survival(DFS) rate and overall survival (OS) rate were statistically higher for the group of women treated with combination of CT-RT (92-95%) compared to the women treated with RT alone (65-72%), treated with CT alone (67-74%) and women who received no adjuvant therapy (38-45%). The multivariate analysis revealed that carcinosarcoma histology was associated with shortened DFS and OS (P = 0.001, P = 0.002). On the other hand, being at stage Ia (P = 0.01, P = 0.04) and receiving adjuvant treatment of CT-RT combination (P = 0.005, P = 0.002) appeared to lead to increased DFS and OS rates. CONCLUSIONS: We identified that a combination treatment of chemotherapy and radiotherapy is superior compared to other postoperative adjuvant treatment approaches concerning PFS, OS and recurrence rates in stages I-II of type II endometrial cancers and uterine carcinosarcoma.

Intraoperative ultrasound reduces the need for re-excision in breast-conserving surgery.

BACKGROUND: The purpose of this study was to evaluate ultrasound-guided surgery for palpable breast cancer by comparing the standard palpation-guided surgery in terms of the extent of healthy breast tissue resection, the percentage of tumor-free margins, and cosmetic outcomes. METHODS: This was a prospective, observational cohort study conducted from January 2009 to July 2011. Breast cancer patients, diagnosed via biopsy, were operated in guidance with either ultrasound or palpation. Patient demographics, tumor features, intraoperative findings, pathologic and cosmetic results, intraoperative-measured ultrasound margins, and pathology margins were compared. RESULTS: Ultrasound (US)-guided lumpectomy was performed on 84 women and palpation-guided lumpectomy on 80 women. Patient demographics and tumor characteristics showed no differences. The rate of re-excision was 17 % for the palpation-guided surgery group, and 6 % for the US-guided group (p = 0.03). There was good correlation between the closest margins recorded by US and pathology margins (r = 0.76, p = 0.01). Volume of resection was significantly larger in the palpation-guided group despite the similar size of tumors (p = 0.048). Cosmetic outcome of surgery was equivalent between groups. CONCLUSIONS: Intraoperative ultrasound guidance for excision of palpable breast cancers is feasible and gives results in terms of pathologic margins that are comparable with those achieved by standard palpation-guided excisions.

Extrapulmonary lymphangioleiomyomatosis mimicking lymphoma metastatic to uterus.

Lymphangioleiomyomatosis is a very rare disease that primarily affects the lungs. The atypical smooth muscle cells in these tumors stain both with smooth muscle markers and melanocytic markers characteristically like their counterparts in other members of the PEComa family. Extrapulmonary lymphangioleiomyomatosis, especially without pulmonary involvement, is extremely rare. The clinical importance of lymphangioleiomyomatosis lies in the fact that it may mimic other malignant diseases, such as lymphoma or sarcoma. Here, we report a case of extrapulmonary lymphangioleiomyomatosis without involvement of the lungs, in a patient pre-diagnosed as having lymphoma metastasized to the uterus or uterine sarcoma.

Fibroadenomatosis involving bilateral breasts and axillary accessory breast tissues in a renal transplant recipient given cyclosporin A.

We present the mammographic and sonographic findings in a case of fibroadenomatosis involving both breasts and axillae in a renal transplant patient after 16 years of treatment with cyclosporin A. Awareness of the fact that cyclosporin A may induce the formation of fibroadenomas, including in accessory breast tissue, is important for correct diagnosis and preventing unnecessary intervention.

Incremental value of magnetic resonance imaging for breast surgery planning.

PURPOSE: The aim of this study was to evaluate the effect of breast magnetic resonance imaging (MRI) on preoperative or intraoperative surgical planning. METHODS: One hundred and sixty females with breast cancer were enrolled in the study. The contribution of MRI compared to MMG and USG, their histopathological concordance, and their impact on surgical treatment were evaluated prospectively. RESULTS: In 48 (30.0%) of the patients, MRI identified suspicious lesions that were not detected by MMG and USG. The diagnosis by MRI was accurate in 17 (10.6%) of them, while in remaining 31 patients (19.4%) the additional lesions found by MRI and interpreted as malignant were found not to be malignant. The pathological accordance of MRI and MMG compared with USG were 69.3 and 70.0%, respectively, whereas individually, MMG and USG were in accordance with the pathological examination in 52.9 and 67.9% of the cases, respectively. CONCLUSIONS: Assessment of the tumor size, multifocality, multicentricity, and presence of ductal carcinoma in situ by MRI may lead to misinterpretations in the majority of patients. The surgical approach should not be changed based solely on MRI findings. An accurately interpreted MMG combined with USG may be sufficient in most cases.

The Role of Morphology in Predicting Fumarate Hydratase-deficient Uterine Leiomyomas in Young Women.

Hereditary leiomyomatosis and renal cell carcinoma is caused by germline mutations in the fumarate hydratase (FH) gene and is associated with an increased incidence of leiomyomas and a potentially aggressive variant of renal cell carcinoma. Pathologic evaluation of uterine leiomyoma can provide an opportunity for early recognition of the syndrome. We reviewed all archived slides of the cases to identify the characteristic morphologic features described for FH-deficient leiomyomas. We performed immunohistochemistry on whole sections of patients with uterine leiomyoma to evaluate for both FH and 2-succinocysteine (2SC) expression. Of the 106 cases, 19 showed the characteristic eosinophilic nucleoli with perinuclear halos, and 24 revealed a characteristic eosinophilic cytoplasmic inclusion consisting of pink globules present within the cytoplasm. Both of these morphologic findings were present together in 15 cases, and hemangiopericytomatous vessels were detected in 23 cases. The loss of FH protein expression was detected in 14 out of 106 cases (13%), and 13 out of 106 cases (12%) were positive for 2SC. We detected 10 cases with both 2SC-positive and FH expression loss. The presence of eosinophilic nucleoli with perinuclear halos and eosinophilic cytoplasmic inclusion was associated with both loss of FH protein expression and 2SC positivity ( P < 0.001). These findings underscore the importance of hematoxylin and eosin-based predictive morphology in FH-deficient uterine leiomyomas. Therefore, morphologic assessment of uterine leiomyomas for features of FH deficiency can serve as a screening tool for hereditary leiomyomatosis and renal cell carcinoma syndrome, allowing patients to be divided according to their hereditary risk assessment.

Ductal Carcinoma In Situ Arising in Sentinel Axillary Lymph Nodes Excised From Patients With Breast Carcinoma - A Potential Diagnostic Pitfall. Report of Two Cases.

We present two cases of ductal carcinoma in situ (DCIS) that arose in axillary lymph nodes excised as the sentinel lymph node from two patients with breast carcinoma. The patient ages were 72 and 36 years and both patients underwent mastectomy and axillary lymph node dissection. In addition to DCIS in the sentinel lymph node, the first patient had a wide DCIS and microinvasion in the ipsilateral breast and a micrometastasis in another sentinel lymph node. The second patient was operated on after neoadjuvant chemotherapy and had DCIS and a small focus of invasion, in addition to invasive and in situ ductal carcinoma in the lymph node having signs of chemotherapy-induced regression. The presence of DCIS was confirmed by use of the immunohistochemical method with antibodies against myoepithelial cells. As a potential source of cellular origin, DCIS was accompanied by benign epithelial cell clusters in the lymph node in both cases. Morphologic and immunohistochemical features were similar in breast and lymph node neoplasms. We conclude that DCIS may rarely develop from benign epithelial inclusions in the axillary lymph node and is a potential diagnostic pitfall in cases having ipsilateral breast carcinoma.

Evaluation of immune density, PD-L1, and CXCR4 expressions in metaplastic breast carcinoma to predict potential immunotherapy benefit.

Metaplastic breast carcinoma (MBC) -rare but fatal subtype of invasive breast carcinomas- provides limited benefit from conventional triple-negative breast carcinoma chemotherapy. We aimed to determine the immune density of this tumor and to evaluate of programmed death-ligand 1 (PD-L1) and chemokine receptor type 4 (CXCR4) expressions to determine whether it would benefit from immunotherapy. Clinicopathological characteristics of 85 patients diagnosed as MBC between 1997 and 2017 were retrospectively assessed. We evaluated the immunohistochemical expression of PD-L1 and CXCR4, and the extent of tumour infiltrating lymphocytes (TILs), with survival data. TILs groups were statistically significantly associated with lymph node status, histological subtype, squamous component, local recurrence and/or systemic metastasis, and disease-related deaths (p < 0.05). PD-L1 positivity in immune cells (ICs) has a statistically significant relationship with the presence of squamous component (p = 0.011) and HER2 positivity (p = 0.031). PD-L1 positivity in tumor cells (TCs) was found to be significantly more frequent in high-TILs density (p = 0.003). PD-L1 combined positive score was significantly associated with the tumors containing high-TILs density (p = 0.012) and squamous component (p = 0.035). Disease-free and disease-specific survival rates were found to be longer for the cases displaying PD-L1 positivity in ICs; and also PD-L1 positivity in ICs was found to be an independent prognostic factor. When the expression of CXCR4 was compared with clinicopathological and survival parameters, no statistically significant association was found (p > 0.05). Based on the results of this retrospective study, PD-L1 and TILs appear to be prognostic. This study provides rationale for further studies to determine whether a subset of patients with metaplastic breast cancer could derive a meaningful benefit from immune-targeting therapies.

Diverging prognostic effects of CD155 and CD73 expressions in locally advanced triple-negative breast cancer.

Background: Immune checkpoint inhibition, combined with novel biomarkers, may provide alternative pathways for treating chemotherapy-resistant triple-negative breast cancer (TNBC). This study investigates the expression of new immune checkpoint receptors, including CD155 and CD73, which play a role in T and natural killer (NK) cell activities, in patients with residual TNBC after neoadjuvant chemotherapy (NAC). Methods: The expression of biomarkers was immunohistochemically examined by staining archival tissue from surgical specimens (n = 53) using specific monoclonal antibodies for PD-L1, CD155, and CD73. Results: Of those, 59.2% (29/49) were found to be positive (>1%) for PD-L1 on the tumour and tumour-infiltrating lymphocytes (TILs), while CD155 (30/53, 56.6%) and CD73 (24/53, 45.3%) were detected on tumours. Tumour expressions of CD155 and CD73 significantly correlated with PD-L1 expression on the tumour (p = 0.004 for CD155, p = 0.001 for CD73). Patients with CD155 positivity ≥10% were more likely to have a poor chemotherapy response, as evidenced by higher MDACC Residual Cancer Burden Index scores and Class II/III than those without CD155 expression (100% vs 82.6%, p = 0.03). At a median follow-up time of 80 months (range, 24-239), patients with high CD73 expression showed improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) rates compared to those with low CD73 expression. In contrast, patients with CD155 (≥10%) expression exhibited a decreasing trend in 10-year DFS and DSS compared to cases with lower expression, although statistical significance was not reached. However, patients with coexpression of CD155 (≥10%) and low CD73 were significantly more likely to have decreased 10-year DFS and DSS rates compared to others (p = 0.005). Conclusion: These results demonstrate high expression of CD73 and CD155 in patients with residual tumours following NAC. CD155 expression was associated with a poor response to NAC and poor prognosis in this chemotherapy-resistant TNBC cohort, supporting the use of additional immune checkpoint receptor inhibitor therapy. Interestingly, the interaction between CD155 and CD73 at lower levels resulted in a worse outcome than either marker alone, which calls for further investigation in future studies.

Prognostic Implications of Immune Infiltrates in the Breast Cancer Microenvironment: The Role of Expressions of CTLA-4, PD-1, and LAG-3.

The assessment of immune infiltrate in invasive breast carcinomas (IBCs), most commonly referred to as tumor infiltrating lymphocytes (TILs), is gaining importance in the current quest for optimal biomarker selection and prediction of prognosis. In this study, the impact of intensity of TILs and expressions of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), and lymphocyte activation gene 3 (LAG-3) in a group of breast carcinomas with regards to the prognosis and conventional pathologic parameters was scrutinized. For this purpose, 238 patients with IBCs containing different proportions of TILs were included in the study. IBCs with higher proportion of TILs were usually grade III carcinomas and correlated with poor prognostic features like receptor negativity, nonluminal intrinsic subtype (P<0.001). Similarly, PD-1 and LAG-3 positivity in immune cells (IC) were more likely to be positive in grade III IBC cases (P=0.004). In addition, PD-1 positivity in IC was more frequent in estrogen receptor-negative tumors (P=0.011) whereas LAG-3 positivity increased in large sized, estrogen receptor and progesterone receptor-negative tumors (P=0.050, 0.023, 0.04, respectively). CTLA-4 positivity in IC was more frequent in large-sized tumors (P=0.040). These 3 markers were also significantly associated with one another and also with the amount of TILs. In survival analysis, cases with prominent-TILs especially displaying CTLA-4, PD-1, and LAG-3 positivity appeared to have longer disease-free and overall survival (CTLA-4: P=0.027, P=0.024; PD-1: P=0.030, P=0.026; LAG-3: P=0.006, P=0.012, respectively). We conclude that the high proportion of TILs and as well as high expression of CTLA-4, PD-1, and LAG-3 in TILs have positively contributed to the outcome despite their correlation with poor conventional pathologic features. We suggest that these 3 immune markers can be used for the determination of proper treatment as well as prediction of prognosis in IBCs with TILs.

Abbreviated and Standard Breast MRI in Neoadjuvant Chemotherapy Response Evaluation: A Comparative Study.

OBJECTIVES: This study aims to investigate the efficacy of abbreviated breast magnetic resonance imaging (MRI) in neoadjuvant chemotherapy (NAC) response evaluation. METHODS: MR images of 50 locally advanced breast cancer patients who underwent standard protocol (SP) breast MRI before and after NAC were re-evaluated retrospectively. Abbreviated protocol (AP) was obtained by extracting images from SP and then evaluating them in a separate session. Protocols were compared with the histological findings after surgery as the reference standard. RESULTS: A statistically significant difference was found between the two protocols in response evaluation by the McNemar test (p=0.018). However, the Kappa value was 0.62 (p<0.001), which indicates substantial agreement. No statistically significant differences were found between the two protocols (AP and SP) and pathological results in the McNemar test (p=0.12, p=0.60, respectively). Kappa values were 0.48 (p<0.001) and 0.60 (p<0.001), respectively, which indicates moderate agreement for both protocols with higher values by SP evaluation. The residual maximum median diameters were smaller than the pathology, with both protocols (p<0.001). CONCLUSION: Despite the statistical differences, there was a significant correlation in response evaluation between the two protocols. The pathological results were moderately correlated with both protocols, with SP slightly higher. However, the residual maximum median diameters were smaller than the pathology with both protocols. These results may limit the use of AP in evaluating the local extent of the tumor, especially in patients who will undergo breast-conserving surgery.