The immune microenvironment characterisation and dynamics in hormone receptor-positive breast cancer before and after neoadjuvant endocrine therapy.

BACKGROUND: Oestrogen receptor positive (ER+)/HER-2 negative breast cancer (BC) is considered to be an immunologically cold tumour compared to triple negative breast cancer. Therefore, the tumour microenvironment (TME) of ER+/HER-2 negative BC is understudied. The aim of this project is to investigate the TME and the immune response during neoadjuvant endocrine therapy (NET) and to correlate this with the treatment response in a real life setting. METHODS: Expression of immune checkpoint receptors and immune cells was examined immunohistochemically, pre- and post-NET in a cohort of 56 ER+/HER-2 negative BC patients. They were treated with tamoxifen (n = 16), an aromatase inhibitor (n = 40) or a combination of an aromatase inhibitor with a PI3K inhibitor (n = 11) for a median duration of 6 months (range 1-32 months). Immunohistochemical staining with monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, CTLA-4, CD4, CD68 and FOXP3 were performed. All staining procedures were done according to validated protocols, and scoring was done by a pathologist specialized in breast cancer. Positivity was defined as staining >1% on TILs. Response to NET was evaluated according to tumour size change on imaging and Ki-67 change. RESULTS: The median age was 61.02 (37-90) years. Diameter of tumour size decreased with a mean of 8.1 mm (-16 mm to 45 mm) (p < 0.001) during NET and the value of Ki-67 value decreased with a median of 9 after NET (p < 0.001). An increase in PD-L1 expression after NET showed a trend towards significant (p = 0.088) and CD-4+ T cells significantly increased after NET (p = 0.03). A good response to NET defined as a decrease in tumour size and/or decrease of Ki-67 was found to be associated with a longer duration of NET, a change of CD4+ T-cells and a higher number of CD68+ tumour-associated macrophages before the start of NET. CONCLUSION: The immune microenvironment plays an important role in ER+/HER-2 negative BC. NET influences the composition and functional state of the infiltrating immune cells. Furthermore, changes in the immune microenvironment are also associated with treatment response.

The role of loco-regional treatment in long-term quality of life in de novo stage IV breast cancer patients: protocol MF07-01Q.

BACKGROUND/OBJECTIVE: Since more solid evidence has emerged supporting the effectiveness of loco-regional treatment (LRT), clinicians consider LRT a treatment option for selected de novo stage IV breast cancer (BC) patients. This is the first report on long-term quality of life (QoL) in a cohort of patients who were randomized to receive either LRT and then systemic treatment (ST) or ST alone in the protocol MF07-01. We aimed to evaluate QoL in patients living at least 3 years since randomization using scores from the SF-12 health survey. METHODS: SF-12 (V2) forms were completed during visits of patients who were living 36 months after the randomization. We first calculated PCS-12 (Physical Health Composite Scale) and MCS-12 (Mental Health Composite Scale) scores from de novo stage IV BC patients and compared them with the scores of patients diagnosed with stage I-III BC who lived more than 3 years. Further, PCS-12 and MCS-12 scores were compared between the LRT and ST groups with de novo stage IV BC. Additionally, general health, physical functioning, role functioning, bodily pain, vitality, mental health, and social functioning were evaluated and compared between the groups. Considering age-related changes in QoL, we also compared PCS-12 and MCS-12 scores of patients below or above 55 and 65 years of age. Responses to four additional questions (compare your physical health, mental health, daily activities, and energy currently vs. at diagnosis of BC) were recorded, considering cultural differences. RESULTS: There were 81 patients in this analysis; 68% of patients (n = 55) had LRT, and 32% (n = 26) received ST. General health was good or very good in 62% (n = 34) in the LRT group and 66% (n = 17) in the ST-only group (p = 0.63). Mean PCS-12 score was 40.8 + 1.6, and mean MCS-12 score was 43.4 + 2.0 (p = 0.34 and p = 0.54, respectively). PCS-12 and MCS-12 score difference was lower than that of the general Turkish population (PCS-12 = 49.3 + 12.8 and MCS-12 = 46.8 + 13.0) and stage I-III BC patients (PCS-12 = 51.1 ± 0.5, MCS-12 = 45.7 ± 0.6). PCS-12 and MCS-12 scores were similar between the LRT and ST-only groups in patients younger and older than 55 and 65, but QoL scores were much better in stage I-III BC patients younger than 65 when compared to the scores of those with de novo stage IV BC. Although treatment with or without LRT did not affect physical health, mental health, daily activities, and energy at 3 years vs. at diagnosis of BC in de novo stage IV BC patients (p > 0.05), these variables were significantly better in stage I-III BC patients (p < 0.001). CONCLUSION: The current MF07-01Q study demonstrates that patient who had LRT has similar physical and mental health outcomes compared to ST only in a cohort of patients who lived longer than 3 years. Trial registration This study is registered on clinicaltrials.gov with identifier number NCT00557986.

The immunologic aspects in hormone receptor positive breast cancer.

BACKGROUND: Although hormone receptor positive/HER2-negative (HR +/HER2-) breast cancer is the most diagnosed breast cancer type, the immunologic aspects HR positive breast cancer (BC) has been neglected until recently.  The purpose of this paper is to review the current knowledge of the immune environment in HR positive BC and the potential use of immunotherapy in these patients. METHOD: A computer-based literature research was carried out using PubMed, American Society of Clinical Oncology Annual Meeting (ASCO) and San Antonio Breast Cancer Symposium (SABCS). RESULTS: The tumour microenvironment (TME), with infiltrating immune cells, plays an important role in HR positive BC. However, the effects of these immune cells are different in the luminal cancers compared to the other breast cancer types. Even though PD-1 and PD-L1 are less expressed in HR positive BC, pathological complete response (pCR) was more often seen after PD-1 inhibitor treatment in patients with an increased expression. The studies support the assertion that endocrine therapy has immunomodulatory effect. CONCLUSION: The reviewed literature indicates that immune cells play an important role in HR positive BC. Considerably more research is needed to determine the real effect of the TME in this patient group.

Triple-negative breast cancer-Role of immunology: A systemic review.

Recently, the complex role of immune therapy has been the target of increased attention in breast cancer, particularly in triple-negative breast cancer (TNBC). Although TNBC is sensitive to chemotherapy, the recurrence and mortality rates are worse compared with the other breast cancer types. In addition, TNBC still lacks targeted treatment options. With the improved understanding of the immune system in TNBC, it is expected that new predictive and prognostic markers will be identified, and innovative treatment modalities will be developed. The aim of this review was to provide an overview of the effector cells in the TNBC's microenvironment and to highlight a novel approach to treat this kind of cancer. A computer-based literature research was carried out using PubMed, American Society of Clinical Oncology Annual Meeting (ASCO) and San Antonio Breast Cancer Symposium (SABCS). To date, studies have shown that tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) play a very important role in the TNBC's microenvironment. Tumor-infiltrating lymphocytes can even be considered as biomarkers to predict chemotherapy response in TNBC. Furthermore, TNBC was shown to have immune active subtypes, and therefore, the use of immunotherapy may be an attractive treatment approach. In this respect, several randomized studies have been designed or are currently ongoing to explore the combination of chemotherapy with immunotherapy in TNBC. Combination of chemo- and immunotherapy is likely to be beneficial in a subgroup of patients with TNBC.

Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01.

BACKGROUND: The MF07-01 trial is a multicenter, phase III, randomized, controlled study comparing locoregional treatment (LRT) followed by systemic therapy (ST) with ST alone for treatment-naïve stage IV breast cancer (BC) patients. METHODS: At initial diagnosis, patients were randomized 1:1 to either the LRT or ST group. All the patients were given ST either immediately after randomization or after surgical resection of the intact primary tumor. RESULTS: The trial enrolled 274 patients: 138 in the LRT group and 136 in the ST group. Hazard of death was 34% lower in the LRT group than in the ST group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.49-0.88; p = 0.005). Unplanned subgroup analyses showed that the risk of death was statistically lower in the LRT group than in the ST group with respect to estrogen receptor (ER)/progesterone receptor (PR)(+) (HR 0.64; 95% CI 0.46-0.91; p = 0.01), human epidermal growth factor 2 (HER2)/neu(-) (HR 0.64; 95% CI 0.45-0.91; p = 0.01), patients younger than 55 years (HR 0.57; 95% CI 0.38-0.86; p = 0.007), and patients with solitary bone-only metastases (HR 0.47; 95% CI 0.23-0.98; p = 0.04). CONCLUSION: In the current trial, improvement in 36-month survival was not observed with upfront surgery for stage IV breast cancer patients. However, a longer follow-up study (median, 40 months) showed statistically significant improvement in median survival. When locoregional treatment in de novo stage IV BC is discussed with the patient as an option, practitioners must consider age, performance status, comorbidities, tumor type, and metastatic disease burden.

The distribution of CD44+/CD24- cancer stem cells in breast cancer and its relationship with prognostic factors.

PURPOSE: The purpose of this study was to investigate the correlation between the percentages of CD44+/CD24- cancer stem cells (CSCs) and the clinicopathological and prognostic factors in breast cancer patients. METHODS: Twenty three women who underwent surgery for breast cancer were enrolled in this study. The mean age of the patients was 46.65 years and 52% had early-stage disease. Tumor tissues obtained during surgery were digested enzymatically. CD44+/CD24- cell phenotype was identified by using surface marker antibodies and percentages were determined by surface marker expression of the cells. RESULTS: Sixty five percent of the tumors were positive for estrogen (ER)/ progesterone receptors (PR) and 38% of the tumors were positive for HER-2. All of the patients with hormone receptor positive tumors had ER positive tumors, while only 11 patients had PR positive breast cancer. CD44+/CD24- cells were present in all tumor tissues. The mean proportion of the CD44+/CD24- cells was 1.43±1.6. The mean percentages of CD18+ cells and MUC1+ were 27.9±26.5% and 6.07±11.34%, respectively. The percentage of CD18+ cells was significantly higher in PR positive tumors (p=0.042). There was no significant correlation between the percentage of CD44+/CD24- cells and clinicopathological features. CONCLUSION: This study showed that CD44+/CD24- cells were present in all tumor tissues. The percentage of CD44+/CD24- cells was higher in early-stage disease, yet without statistical significance. No correlation was found between prognostic factors and the percentage of the CD44+/CD24- cells.

Identification of ApoA1, HPX and POTEE genes by omic analysis in breast cancer.

Breast cancer is the most common cancer among women and accounts for 23% of all female types of cancers. It is well recognized that breast cancer represents a heterogeneous group of tumors, and the molecular events involved in the progression to cancer remain undetermined. Moreover, available prognostic and predictive markers are not sufficient for the accurate determination of the risk for many breast cancer patients. Thus, it is necessary to discover new molecular markers for accurate prediction of clinical outcome and individualized therapy. In the present study, we performed omics-based whole-genome trancriptomic and whole proteomic profiling with network and pathway analyses of breast tumors to identify gene expression patterns related to clinical outcome. A total of 20 samples from tumors and 14 normal appearing breast tissues were analyzed using both gene expression microarrays and LC-MS/MS. We identified 585 downregulated and 413 upregulated genes by gene expression microarrays. Among these genes, HPX, POTEE and ApoA1 were the most significant genes correlated with the proteomic profile. Our data revealed that these identified genes are closely related to breast cancer and may be involved in robust detection of disease progression.

Necessity for additional incisions with the cervical collar incision to remove retrosternal goiters.

PURPOSE: Retrosternal goiters (RSGs) can be removed transcervically, but additional incisions are sometimes necessary. We examined the factors determining the need for additional incisions to remove an RSG goiter, based on our experience and on an algorithm. METHODS: Among 499 patients who underwent surgery for a goiter, 52 (10.4%) had an RSG removed via a collar incision. Additional incisions were necessary in 11 patients (21% of those with an RSG and 2.2% overall): a partial sternotomy in 4, total sternotomy in 5, and right thoracotomy in 2. RESULTS: Recurrent nerve paralysis developed in two patients and one patient had a tracheal laceration. There was no mortality. A diagnosis of adenomatous goiter was confirmed in all patients. CONCLUSIONS: Additional incisions can be made if thyroidectomy cannot be done transcervically and if the goiter extends to the level of the aortic arch. If the thyroid gland extends below the aortic arch and the lateral diameter of the goiter is greater than 10 cm, a partial sternotomy may be required. Total sternotomy is needed when an RSG extends caudally to the azygos vein, if it is located in the retrotracheal or retroesophageal space, or if it is recurrent or ectopic. Coexisting lung disorders and goiters extending to the left atrium also require thoracotomy.

Clinical assessment of 324 breast cancer cases in two centers between the years of 1992 and 2002.

The records of the 324 patients with breast cancer; diagnosed and followed in two different University Hospital between years of January 1992 and January 2002 were reviewed retrospectively. The median age of the patients was 49.0+/-12.5 years, with the range of 18 and 90 years. The most frequently seen age interval of the patients was 40 and 49 years. The most frequently seen symptom and physical examination finding of the patients were breast mass. Breast cancer was diagnosed in 324 women, 173 in the left breast and 151 in the right breast. At the hospital admission percentages of the patients' disease stages were as follows: I (2.8%), IIA (30.0%), IIB (24.0%), IIIA (19.8%), IIIB (11.4) and IV (12.0%). The most frequently seen histopathological diagnosis was infiltrative ductal carcinoma (84.4%). Axillary lymph node metastasis was found in 61.7% of the patients. Primary therapeutic options and percentages were surgical therapy (78.5%), systemic chemotherapy (17.5%) and radiotherapy (4%). Systemic chemotherapy was given to 81.2% of the patients. From the files, estrogen receptor status was known in 311 and positive in 128 (41.2%) of them. Tamoxifen was given patients who had positive estrogen receptor. The five-year survival rate of the patients was calculated as 75.9%.

Is minisite cholecystectomy less traumatic? Prospective randomized study comparing minisite and conventional laparoscopic cholecystectomies.

The main objectives of minisite cholecystectomy (MC) are to have smaller incisions, better cosmetic results, less trauma, and a lower morbidity rate. This prospective randomized study compares MC with conventional laparoscopic cholecystectomy (CLC) in terms of surgical trauma and cosmetic results in 44 patients. Conversion from MC to CLC was required in five patients. No conversion to open surgery was needed in the CLC group. The average operating time was slightly longer in the MC group, but the difference was not statistically significant (81 minutes versus 72 minutes, p = 0.22). The population characteristics, postoperative respiratory function measurements, pain scores, and analgesic requirements were similar in the two groups. The average score for scar tissue was significantly lower in the MC group (0.73 versus 1.93, p = 0.0045). Only the cosmetic results of MC were superior to CLC. This technique could be a feasible alternative procedure in patients seeking better cosmetic results. However, further studies with larger sample sizes are needed to evaluate the postoperative morbidity of MC.

Effects of granulocyte colony-stimulating factor (g-csf) on neutrophil phagocytosis during experimental obstructive jaundice.

BACKGROUND: Obstruction ofthe extrahepati(biliary tree produces profound depression of many components ofthe immune system. G-CSF improves diseasedfiinction fneutrophils in various conditions. In this study, we planned to investigate the changes on neutrophil phagocytosis in obstruct;ve jaundice and the effect ofG-CSF adm;nistration on thisfiinction. METHODS: Rats were divided into 5 groups as follows: the sham group and four other groups that underwent double ligation and division of common bile duct. Two of these four groups (Group 3 and 5) received G-CSF during experiment. Neutrophil hagocytosis index was determinedforgroup2and 3 attheend ofthe 15 daysand forgroup 1, 4and 5 attheend of the21 days. RESULTS: Neutrophil phagocytosis index significantly increased at the end ofthe 15th day after the bile duct ligation (Group 2) and significantly decreased at the end ofthe 21th day after the bile duct ligation (Group 4). Neutrophil phagocytosis index in G-CSF-treated groups was significantly increased at the end ofthe 15'h days (Group 3) and increased at the end of the 21th day (Group 5). CONCLUTION: As a result, neutrophil phagocytosis index is improved if G-CSF is administered later in the course of prolonged jaundice.