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Interleukin-33 (IL-33), a member of the interleukin-1(IL-1) family of cytokines, remains poorly understood in the context of human breast cancer and its impact on treatment outcomes. This study aimed to elucidate IL-33 expression patterns within tumor samples from a cohort of Brazilian female breast cancer patients undergoing neoadjuvant chemotherapy while exploring its correlation with clinicopathological markers. In total, 68 samples were meticulously evaluated, with IL-33 expression quantified through a quantitative polymerase chain reaction. The findings revealed a substantial upregulation of IL-33 expression in breast cancer patient samples, specifically within the Triple-negative and Luminal A and B subtypes, when compared to controls (healthy breast tissues). Notably, the Luminal B subtype displayed a marked elevation in IL-33 expression relative to the Luminal A subtype (p < 0.05). Moreover, a progressive surge in IL-33 expression was discerned among Luminal subtype patients with TNM 4 staging criteria, further underscoring its significance (p < 0.005). Furthermore, chemotherapy-naïve patients of Luminal A and B subtypes exhibited heightened IL-33 expression (p < 0.05). Collectively, our findings propose that chemotherapy could potentially mitigate tumor aggressiveness by suppressing IL-33 expression in breast cancer, thus warranting consideration as a prognostic marker for gauging chemotherapy response and predicting disease progression in Luminal subtype patients. This study not only sheds light on the intricate roles of IL-33 in breast cancer but also offers valuable insights for future IL-33-related research endeavors within this context. [ABSTRACT FROM AUTHOR]

Metastatic luminal B HER2-negative breast cancer (HR+/HER2- mBC) occupies a leading place in the global structure of morbidity and mortality among women. The current gold standard of first-line treatment is the combination of CDK4/6 inhibitors with aromatase inhibitors, among which ribociclib with letrozole is distinguished. According to the MONALEESA-2 study, the addition of ribociclib to letrozole significantly increased the median overall survival to 63.9 months, reducing the risk of death by 24%. The safety profile of the combination is manageable, and the development of adverse events led to the interruption of therapy only in 7.5% of cases. A study of the actual clinical practice of CompLEEment-1 also confirmed the safety and effectiveness of the combination. Maintaining and improving the quality of life is one of the main tasks in the treatment of patients with HR+/HER2- mBC. According to the MONALEESA-2 study, the addition of ribociclib significantly affects the maintenance of quality of life and leads to a decrease in the intensity of pain syndrome. The published data allowed us to assign a combination of ribociclib and letrozole 4 points on the ESMO-MCBS scale. The safety of long-term use of the combination in the first line of treatment illustrated by clinical observation. The patient's progression-free survival during therapy was 40 months, which significantly exceeds the data of the MONALEESA-2 and CompLEEment-1 studies. The maximum effect (partial response according to RECIST 1.1 -40%) achieved after 24 weeks and persisted for 24 months. Clinically, the patient noted a decrease in the severity of the pain syndrome after 8 weeks of therapy. Against the background of therapy, it was possible to maintain the quality of life without sacrificing antitumor efficacy.

Rationale and Objectives: The aim of the present study was to investigate the association between Luminal A and Luminal B molecular subtypes and radiomic features of dynamic contrast‑enhanced magnetic resonance imaging in patients with invasive breast cancer.Materials and Methods: Seventy-three patients with histopathologically proven invasive ductal cancer (IDC) were selected. Tumors were classified into molecular subtypes: Luminal A (estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive, human epidermal growth factor receptor type 2 (HER2) -negative, proliferation marker Ki-67<20) and Luminal B (ER-positive and/or PR-positive, HER2-positive or HER2-negative with high Ki-67 ≥20). A total of 81 tumoral lesions were evaluated on T1-weighted fat-suppressed sagittal post-contrast late-phase MRI images after the required "pre-process" steps and 3D segmentations were made. Forty-three radiomic features including: 1 conventional, 4 shape, 6 histogram, 7 Grey-Level Co-occurrence Matrix (GLCM), 11 Grey-Level Run-Length Matrix (GLRLM), 3 Neighborhood Grey-Level Difference Matrix (NGLDM), 11 Grey-Level Zone-Length Matrix (GLZLM) were extracted by using the software LIFEX.Results: A statistically significant difference was found in radiomic features including; a) Histogram: "skewness", b) Shape: "volume-ml, volume-voxel," c) GLCM: "entropy.log10, entropy.log2, energy", d) GLRLM: "GLNU, RLNU, HGRE," e) NGLDM: "busyness," f) GLZLM: "GLNU, HGZE, ZLNU, SZE" between two different molecular subtypes. The model combining Shape-volume (ml) and GLZLM-HGZE yielded 0.746 area under the curve (AUC), 0.744 sensitivity, 0.643 specificity and 0.694 accuracy.Conclusion: Radiomic properties that may distinguish Luminal A and Luminal B molecular subtypes of IDC were identified. The radiomic features were thought to reflect the intratumoral heterogeneity in molecular subtypes. This study demonstrated that the characterization of Luminal A and Luminal B tumors could be made non-invasively by radiomics analysis. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33), a member of the interleukin-1(IL-1) family of cytokines, remains poorly understood in the context of human breast cancer and its impact on treatment outcomes. This study aimed to elucidate IL-33 expression patterns within tumor samples from a cohort of Brazilian female breast cancer patients undergoing neoadjuvant chemotherapy while exploring its correlation with clinicopathological markers. In total, 68 samples were meticulously evaluated, with IL-33 expression quantified through a quantitative polymerase chain reaction. The findings revealed a substantial upregulation of IL-33 expression in breast cancer patient samples, specifically within the Triple-negative and Luminal A and B subtypes, when compared to controls (healthy breast tissues). Notably, the Luminal B subtype displayed a marked elevation in IL-33 expression relative to the Luminal A subtype (p < 0.05). Moreover, a progressive surge in IL-33 expression was discerned among Luminal subtype patients with TNM 4 staging criteria, further underscoring its significance (p < 0.005). Furthermore, chemotherapy-naïve patients of Luminal A and B subtypes exhibited heightened IL-33 expression (p < 0.05). Collectively, our findings propose that chemotherapy could potentially mitigate tumor aggressiveness by suppressing IL-33 expression in breast cancer, thus warranting consideration as a prognostic marker for gauging chemotherapy response and predicting disease progression in Luminal subtype patients. This study not only sheds light on the intricate roles of IL-33 in breast cancer but also offers valuable insights for future IL-33-related research endeavors within this context.

Abstract Introduction Germline mutations in BRCA1/2 are the most common cause of hereditary breast and ovarian cancer (HBOC) syndrome. Few studies published during the past decade reported the prevalence of germline BRCA mutations in Asian patients with breast cancer. We aimed to assess the prevalence and characteristics of Thai patients with breast cancer with germline BRCA1/2 mutations. Methods We retrospectively reviewed all breast cancer patients who were tested for germline BRCA1/2 mutations during 2014–2018. BRCA mutations were detected using next‐generation sequencing and confirmed using Sanger sequencing. We analyzed the characteristics of patients with or without BRCA mutations. Disease‐free survival (DFS) and the associated factors were determined. Results Among 67 patients, 12 (18%) were BRCA1/2 carriers (6 each), 4 (6%) harbored variants of uncertain significance, and 51 (76%) were non‐carriers. We discovered two novel BRCA2 frameshift mutations (c.2380delA and c.8855dupT). Mean ages at breast cancer diagnosis of BRCA1, BRCA2, and non‐carriers were 39.8, 46.2, and 42.0 years, respectively. The 12 tumors of BRCA carriers were mainly the luminal‐B subtype. Two of these tumors were HER2‐positive luminal‐B, and the triple‐negative subtype was not detected. After adjusting for stages and luminal subtypes, BRCA carriers experienced worse 3‐year DFS than non‐carriers (81.5% vs. 90.3%, HR 2.04 [0.64–6.49], p = .229). The stage at diagnosis was the sole factor significantly associated with 3‐year DFS (100%, 84.8%, and 72.7%; stages I, II, and III, respectively). Conclusion Thai patients with breast cancer with BRCA1/2 mutations were mainly the luminal‐B subtypes with worse prognosis than those without mutations.

Simple Summary: Molecular subtyping of muscle-invasive bladder cancer (MIBC) via gene expression can improve therapeutic decision-making and disease prognosis. However, the currently used molecular classification tools are based on complex transcriptomic profiling methodology that hinders timely translation to clinical practice. In this study, we evaluated the NanoString nCounter platform and conventional GATA3-CK5/6 immunohistochemistry for the molecular classification of MIBC in primary care settings. The methodologies were highly concordant and allowed us to explore differences in clinicopathologic parameters and prognosis between intrinsic MIBC molecular subtypes in a cohort of 138 MIBCs. Transcriptional profiling of muscle-invasive bladder cancer (MIBC) using RNA sequencing (RNA-seq) technology has demonstrated the existence of intrinsic basal and luminal molecular subtypes that vary in their prognosis and response to therapy. However, routine use of RNA-seq in a clinical setting is restricted by cost and technical difficulties. Herein, we provide a single-sample NanoString-based seven-gene (KRT5, KRT6C, SERPINB13, UPK1A, UPK2, UPK3A and KRT20) MIBC molecular classifier that assigns a luminal and basal molecular subtype. The classifier was developed in a series of 138 chemotherapy naïve MIBCs split into training (70%) and testing (30%) datasets. Further, we validated the previously published CK5/6 and GATA3 immunohistochemical classifier which showed high concordance of 96.9% with the NanoString-based gene expression classifier. Immunohistochemistry-based molecular subtypes significantly correlated with recurrence-free survival (RFS) and disease-specific survival (DSS) in univariable (p  =  0.006 and p  =  0.011, respectively) and multivariate cox regression analysis for DSS (p = 0.032). Used sequentially, the immunohistochemical- and NanoString-based classifiers provide faster turnaround time, lower cost per sample and simpler data analysis for ease of clinical implementation in routine diagnostics. [ABSTRACT FROM AUTHOR]

Breast cancer arising in very young patients may be biologically distinct; however, these tumors have been less well studied. We characterized a group of very young patients (≤ 35 years) for BRCA germline mutation and for somatic mutations in luminal (HER2 negative) breast cancer. Thirteen of 79 unselected very young patients were BRCA1/2 germline mutation carriers. Of the non-BRCA tumors, eight with luminal subtype (HER2 negative) were submitted for whole exome sequencing and integrated with 29 luminal samples from the COSMIC database or previous literature for analysis. We identified C to T single nucleotide variants (SNVs) as the most common base-change. A median of six candidate driver genes was mutated by SNVs in each sample and the most frequently mutated genes were PIK3CA, GATA3, TP53 and MAP2K4. Potential cancer drivers affected in the present non-BRCA tumors include GRHL2, PIK3AP1, CACNA1E, SEMA6D, SMURF2, RSBN1 and MTHFD2. Sixteen out of 37 luminal tumors (43%) harbored SNVs in DNA repair genes, such as ATR, BAP1, ERCC6, FANCD2, FANCL, MLH1, MUTYH, PALB2, POLD1, POLE, RAD9A, RAD51 and TP53, and 54% presented pathogenic mutations (frameshift or nonsense) in at least one gene involved in gene transcription. The differential biology of luminal early-age onset breast cancer needs a deeper genomic investigation.

Purpose: To evaluate the influence of obesity on clinicopathological characteristics of breast cancer; to explore the effect of obesity on the prognosis and performance of endocrine therapy in breast cancer patients. Methods: Patients with luminal/HER2-negative early breast cancer were included and categorized into the non-obese (BMI<28kg/m2) and obese (BMI≥28kg/m2) groups according to body mass index (BMI). Clinicopathological characteristics and treatment modalities were compared between groups. Interaction of adjuvant endocrine therapy with obesity was analyzed. Results: A total of 2,875 patients were included: 2,598 non-obese and 277 obese. A higher rate of patients with comorbidities (OR: 2.83, 95%CI 2.13-3.74, P <0.001) or PR-positive tumor (OR: 1.63, 95%CI 1.03-2.58, P =0.037) were identified in the obese group. Obesity was not associated with disease recurrence (P =0.839) or overall survival (P =0.140) in the whole population. Subgroup analysis did show an association with worse relapse-free survival (RFS, HR 3.48, 95%CI 1.31-9.22, P =0.012) and overall survival (OS, HR 4.67, 95%CI 1.28-16.95, P =0.019) in luminal A breast cancer. These results could not be reproduced in the luminal B subtype with a RFS (HR 0.78, 95%CI 0.41-1.49, P =0.454) or OS (HR 1.17, 95%CI 0.50-2.74, P =0.727). Furthermore, obesity did not impact endocrine therapy effectiveness in Tamoxifen or the aromatase inhibitor group (RFS: interact P =0.381; OS: interact P =0.888). Conclusions: The impact of obesity on prognosis interacted with luminal subtype status in Chinese breast cancer patients which was not related with endocrine treatment modality. [ABSTRACT FROM AUTHOR]

Transitional cell carcinoma of the bladder is a common malignancy with an estimated 549 393 new cases occurring in 2018 alone. Both non–muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) show high recurrence and progression rates, and therefore impose a great burden on patients and health care systems. Current risk stratification and therapy strategies are predominantly based on clinical and histopathological findings for tumor stage and grade. The chemoresistance and metastasis of low-grade tumors suggest an incomplete understanding of disease mechanisms, despite numerous studies on differentiating molecular subtypes of bladder cancer to identify tumor drivers and potential therapeutic targets. We present a highly unusual course for a low-grade bladder tumor leading to metastasis and death, for which we used postmortem histopathological and molecular analyses to evaluate targetable alterations in key signaling pathways driving the underlying tumor biology.

PurposeTo evaluate the influence of obesity on clinicopathological characteristics of breast cancer; to explore the effect of obesity on the prognosis and performance of endocrine therapy in breast cancer patients.MethodsPatients with luminal/HER2-negative early breast cancer were included and categorized into the non-obese (BMI

Introduction. Breast cancer is the leader in cancer incidence in theRussian Federation. The tumor is considered extremely heterogeneous and the luminal subtypes of breast tumors occupy a special place, since they are considered relatively favorable in therapy and control of the disease.Drug therapy for hormone-positive cancer has undergone significant evolution and new anticancer agents have appeared in the arsenal of the oncologist and have shown promising results compared to classical therapy. The search for predictive markers of the effectiveness of new therapy has become of great importance. This marker turned out to be a mutation in the PIK3CA gene – one of the most frequent genetic disorders in breast cancer cells. According to the literature, the presence of this mutation negatively effects on endocrine therapy for breast tumors.The aim of this study was to analyze the frequency of mutations in the PIK3CA gene among patients with hormone-positive tumors, and the effectiveness of therapy with CDK4/6 inhibitors in this group of patients.Materials and methods. The material for the study of the mutation in the PIK3CA gene was tumor biopsies of 31 patients and clinical data on the response to therapy with CDK4/6 inhibitors and classical hormone therapy.Results and discussion. The results of the work showed a high incidence of the PIK3CA mutation among hormone-positive tumors (45%). The mutation resulted in a decrease in both the median time to progression after radical surgery (from 48.4 ± 7.8 months to 30.1 ± 6.0 months) in patients receiving adjuvant hormone therapy and progression-free survival in patients receiving therapy with CDK4 /6 inhibitors (4.2 months versus 9 months). This confirmed the theory that the PIK3CA mutation negatively affects the outcome of hormone therapy.Conclusions. PIK3CA is an important predictive marker in endocrine therapy for hormone-positive tumors. Its presence not only determines the relatively worse results of treatment, but can also serve as an indication for the appointment of a special series of drugs – inhibitors of this mutation.

Transcriptional profiling of muscle-invasive bladder cancer (MIBC) using RNA sequencing (RNA-seq) technology has demonstrated the existence of intrinsic basal and luminal molecular subtypes that vary in their prognosis and response to therapy. However, routine use of RNA-seq in a clinical setting is restricted by cost and technical difficulties. Herein, we provide a single-sample NanoString-based seven-gene (KRT5, KRT6C, SERPINB13, UPK1A, UPK2, UPK3A and KRT20) MIBC molecular classifier that assigns a luminal and basal molecular subtype. The classifier was developed in a series of 138 chemotherapy naïve MIBCs split into training (70%) and testing (30%) datasets. Further, we validated the previously published CK5/6 and GATA3 immunohistochemical classifier which showed high concordance of 96.9% with the NanoString-based gene expression classifier. Immunohistochemistry-based molecular subtypes significantly correlated with recurrence-free survival (RFS) and disease-specific survival (DSS) in univariable (p = 0.006 and p = 0.011, respectively) and multivariate cox regression analysis for DSS (p = 0.032). Used sequentially, the immunohistochemical- and NanoString-based classifiers provide faster turnaround time, lower cost per sample and simpler data analysis for ease of clinical implementation in routine diagnostics.

With improved survival, more patients with prior breast cancer are at risk of having a second primary cancer diagnosed. The pattern and impact of second primary cancers following breast cancer is important for overall breast cancer therapeutic management. Our study is a first analysis of the trend of second primary tumours over time in terms of incidence, sites with significantly elevated risks and correlation with stage, molecular subtype and therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. Patients and methods: Our study population included 28 patients with prior breast cancer (BC) and second primary tumours, which were diagnosed and treated in our Institution between 2004 and 2017. The criteria for selection were based on the completeness of the documentation of the first treatment for breast cancer, stage of disease, molecular subtype, the site of origin of the second tumours and the survival data. Results: An increased risk of second primary cancer was associated with the 51–60 years age group (53.6%), with the greater prevalence in patients living in urban environments (82.1%). The use of chemotherapy increased the risk of the occurrence of gynecological second malignancies (75%). Our study is a first analysis of the trend of second primary tumours over time in terms of identifying sites with significantly elevated risks and correlation with therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. Conclusions: Our study is a first analysis of the trend of second primary tumours over time in terms of correlation with luminal subtype and stage at diagnosis of primary cancer sites with significantly elevated risks and correlation with therapeutic strategies in postmenopausal women with breast cancer conducted in Eastern Europe. The reported time from primary to second primary malignancy onset, with a significantly higher rate for postmenopausal breast cancer patients, was less than one year (50%). With the advances and wider availability of genetic testing (e.g., gene panels), patients diagnosed with multiple primaries should be increasingly investigated for an underlying cancer predisposition. Postmenopausal women with breast cancer may benefit from increased surveillance and advice to avoid second malignancies.

Purpose: The prognostic role of tumor-infiltrating lymphocytes (TILs) in ER+/HER2− breast cancer (BC) is debated. We evaluated the association of TILs and clinico-pathological features with distant disease-free survival (DDFS) in patients with ER+/HER2− BC treated at a single institution. Patients and methods: A mono-institutional case-cohort series of 987 patients with early ER+/HER2− BC was retrospectively analyzed. TILs were considered both as continuous variable, and dichotomized in low (< 5%) vs high (≥ 5%). The main outcome was DDFS. Median follow-up was 7.5 years (0.1–10). Univariate and multivariable Cox proportional hazards regression with inverse sub-cohort sampling probability weighting were used to evaluate the risk across groups. Results: Median TIL count was 2% (Q1–Q3 1–4%). Higher TILs were positively associated with number of lymph nodes involved (p = 0.003), tumor grade (p < 0.0001), peritumoral vascular invasion (p = 0.003), higher Ki-67 (p = 0.0001), luminal B subtype (p < 0.0001), and chemotherapy use (p < 0.00019). In multivariable regression analysis, only higher Ki-67 expression retained significant association with TILs. At univariate Cox regression analysis, TIL expression (≥ 5% vs. < 5%) was not associated with DDFS (HR 1.08, 95% CI 0.80–1.46, p = 0.62). In patients treated with adjuvant chemotherapy, high TILs were associated with better DDFS (HR 0.52, 95%CI 0.33–0.83, p = 0.006), particularly in the group with Ki-67 ≥ 20% (HR 0.50, 95%CI 0.29–0.86, p = 0.01). Conclusion: High TILs in ER+/HER2− BC are significantly associated with clinico-pathological features of dismal outcome. TIL prognostic value seems different in patients treated with or without chemotherapy. Our findings suggest that the high-risk subgroup might be more immunogenic, thus deserving the exploration of immunotherapy approaches. [ABSTRACT FROM AUTHOR]

Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes. Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%. Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]). No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule. • Dose-dense chemotherapy improves outcome in hormone receptor-positive breast cancer. • Differences in dose-dense effect according to luminal subtype are still unknown. • In the Gruppo Italiano Mammella 2 trial, there was no interaction between luminal subtype and treatment. • Yet, only the luminal B cohort derived survival benefit from dose-dense schedule. • No benefit from dose-dense chemotherapy was observed in the luminal A-like cohort. [ABSTRACT FROM AUTHOR]

Introduction: Our understanding of the granularity of breast cancer (BC) clinical outcomes by biologic subtype may be impaired by limited study follow-up times. Objective: We evaluated the impact of modern immunohistochemistry (IHC)-based BC subtypes on long-term mortality. Method: We used a cohort of 200 women diagnosed with stage I–III BC in the period 1985–1990. Surgical samples underwent centralized pathology review. Multivariate models assessed associations of subtype with overall survival (OS) and BC-related survival (BCRS). Result: 42.0% women had luminal A-like, 32.5% luminal B-like/human epidermal growth factor receptor (HER)2-negative, 8.5% had HER2-positive, and 17.0% had triple-negative BC. 53.0% had tumor size (T) >2 cm and 47.5% had a positive nodal status (N). Over 18.7 years of median follow-up (range 0.3–32.0 years),140 deaths were recorded (75 BC-related). Median OS was longest for patients with luminal A-like tumors (21.2 years; 95% confidence interval [CI] 17.4–24.9]). The luminal B-like/HER2-negative subtype was significantly associated with worse BCRS (adjusted hazard ratio [HR] = 1.86; 95% CI 1.09–3.16). After multivariable analysis, T >2 cm (HR [vs. ≤2 cm] = 1.71 [95% CI 1.03–2.84]) and positive N (HR [vs. negative] = 2.19 [95% CI 1.03–4.65]) impacted BCRS. Conclusion: IHC-defined subtype will continue informing treatment algorithms for BC, until more precise tools like molecular profiling become widely available. Although confirmation in larger and adequately powered studies is warranted, modern surrogate subtype definitions produced a valid long-term prognostic stratification in this mature cohort. [ABSTRACT FROM AUTHOR]

Hormones drive mammary development and function and play critical roles in breast cancer. Epidemiologic studies link prolactin (PRL) to increased risk for aggressive cancers that express estrogen receptor α (ERα). However, in contrast to ovarian steroids, PRL actions on the mammary gland outside of pregnancy are poorly understood. We employed the transgenic NRL-PRL model to examine the effects of PRL alone and with defined estrogen/progesterone exposure on stem/progenitor activity and regulatory networks that drive epithelial differentiation. PRL increased progenitors and modulated transcriptional programs, even without ovarian steroids, and with steroids further raised stem cell activity associated with elevated canonical Wnt signaling. However, despite facilitating some steroid actions, PRL opposed steroid-driven luminal maturation and increased CD61+ luminal cells. Our findings demonstrate that PRL can powerfully influence the epithelial hierarchy alone and temper the actions of ovarian steroids, which may underlie its role in the development of breast cancer.

Luminal subtypes and the 21-gene recurrence score (RS) are important factors in the decision-making process for adjuvant chemotherapy in patients with hormonal receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, their effect on adjuvant chemotherapy decisions in the real world has not been thoroughly investigated, particularly for patients of the luminal A-like subtype with a high RS or the luminal B-like subtype with a low RS. The present study, a total of 772 HR+/HER2− patients who underwent 21-gene testing, were included in a retrospective analysis. The impact of clinicopathological factors and the 21-gene RS on chemotherapy recommendation was analyzed in the whole population and for patients of different luminal subgroups. The results revealed that chemotherapy was highly recommended for patients of younger age, with larger tumor size, node involvement, higher grade, luminal B-like subtype and higher RS. A high RS was identified to be the most important impact factor for chemotherapy recommendation among all patients [odds ratio (OR), 62.54; 95% CI, 25.58–152.92], the luminal A-like group (OR, 435.05; 95% CI, 29.90–6331.06) and the luminal B-like group (OR, 57.20; 95% CI, 22.42–145.96). For patients of the luminal A-like subtype with a high RS or patients of the luminal B-like subtype with low RS, the 21-gene RS was demonstrated to be the most important independent factor for chemotherapy recommendation, with an adjusted OR of 134.52 (95% CI, 10.39–1741.89). In conclusion, luminal subtypes and the 21-gene RS were found to be associated with chemotherapy recommendation for HR+/HER2− patients. For patients with a discordant luminal subtype and 21-gene RS risk, the 21-gene RS score was found to be the most important factor that influences chemotherapy decision, which warrants further clinical evaluation. [ABSTRACT FROM AUTHOR]

Background: More than half of female patients with breast cancer are diagnosed with a luminal subtype of the disease; however, specific characteristics of its metastases to the brain have been not well studied, unlike those of HER2 positive and triple negative subtypes. Aim: A comparative analysis of characteristics of metastatic brain lesions in patients with luminal breast cancer. Materials and methods: The time from surgery for breast cancer to the first recurrence and to metastatic brain lesions (assessed by contrast-enhanced MRI imaging) was measured in 41 patients with luminal subtype of breast cancer (median age, 49.5±9.6 years), depending on a diameter of the primary tumor and numbers of involved axillary lymph nodes. Results: The time interval to occurrence of brain metastases in luminal subtype of breast cancer is not associated with the size of the tumor. If≥4 axillary lymph nodes are involved (N2–3), brain metastases are identified much earlier (p

Breast cancer (BrC) is the most frequent malignancy and the leading cause of cancer death among women worldwide. Approximately 70% of BrC are classified as luminal-like subtype, expressing the estrogen receptor. One of the most common and effective adjuvant therapies for this BrC subtype is endocrine therapy. However, its effectiveness is limited, with relapse occurring in up to 40% of patients. Because microRNAs have been associated with several mechanisms underlying endocrine resistance and sensitivity, they may serve as predictive and/or prognostic biomarkers in this setting. Hence, the main goal of this study was to investigate whether miRNAs deregulated in endocrine-resistant BrC may be clinically relevant as prognostic and predictive biomarkers in patients treated with adjuvant endocrine therapy. A global expression assay allowed for the identification of microRNAs differentially expressed between luminal BrC patients with or without recurrence after endocrine adjuvant therapy. Then, six microRNAs were chosen for validation using quantitative reverse transcription polymerase chain reaction in a larger set of tissue samples. Thus, miR-30c-5p, miR-30b-5p, miR-182-5p, and miR-200b-3p were found to be independent predictors of clinical benefit from endocrine therapy. Moreover, miR-182-5p and miR-200b-3p displayed independent prognostic value for disease recurrence in luminal BrC patients after endocrine therapy. Our results indicate that selected miRNAs’ panels may constitute clinically useful ancillary tools for management of luminal BrC patients. Nevertheless, additional validation, ideally in a multicentric setting, is required to confirm our findings.

Breast cancer (BrC) is the most frequent malignancy and the leading cause of cancer death among women worldwide. Approximately 70% of BrC are classified as luminal-like subtype, expressing the estrogen receptor. One of the most common and effective adjuvant therapies for this BrC subtype is endocrine therapy. However, its effectiveness is limited, with relapse occurring in up to 40% of patients. Because microRNAs have been associated with several mechanisms underlying endocrine resistance and sensitivity, they may serve as predictive and/or prognostic biomarkers in this setting. Hence, the main goal of this study was to investigate whether miRNAs deregulated in endocrine-resistant BrC may be clinically relevant as prognostic and predictive biomarkers in patients treated with adjuvant endocrine therapy. A global expression assay allowed for the identification of microRNAs differentially expressed between luminal BrC patients with or without recurrence after endocrine adjuvant therapy. Then, six microRNAs were chosen for validation using quantitative reverse transcription polymerase chain reaction in a larger set of tissue samples. Thus, miR-30c-5p , miR-30b-5p , miR-182-5p , and miR-200b-3p were found to be independent predictors of clinical benefit from endocrine therapy. Moreover, miR-182-5p and miR-200b-3p displayed independent prognostic value for disease recurrence in luminal BrC patients after endocrine therapy. Our results indicate that selected miRNAs' panels may constitute clinically useful ancillary tools for management of luminal BrC patients. Nevertheless, additional validation, ideally in a multicentric setting, is required to confirm our findings. [ABSTRACT FROM AUTHOR]

Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico‐pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy‐number profiling, and targeted sequencing of 386 cancer‐related genes. The median age of primary tumour diagnosis amongst patients with gynaecological metastases was significantly younger compared to a general breast cancer population (46.5 versus 60 years; p < 0.0001). Median age at metastatic diagnosis was 54.4, time to progression was 4.8 years (range 0–20 years), and survival following a diagnosis of metastasis was 1.95 years (range 0–18 years). Patients had an average of five involved sites (most frequently ovary, fallopian tube, omentum/peritoneum), with fewer instances of spread to the lungs, liver, or brain. Invasive lobular histology and luminal A‐like phenotype were over‐represented in this group (42.8 and 87.5%, respectively) and most patients had involved axillary lymph nodes (p < 0.001). Primary tumours frequently co‐expressed oestrogen receptor cofactors (GATA3, FOXA1) and harboured amplifications at 8p12, 8q24, and 11q13. In terms of phenotype conversion, oestrogen receptor status was generally maintained in metastases, FOXA1 increased, and expression of progesterone receptor, androgen receptor, and GATA3 decreased. ESR1 and novel AR mutations were identified. Metastasis to gynaecological organs is a complication frequently affecting young women with invasive lobular carcinoma and luminal A‐like breast cancer, and hence may be driven by sustained hormonal signalling. Molecular analyses reveal a spectrum of factors that could contribute to de novo or acquired resistance to therapy and disease progression. [ABSTRACT FROM AUTHOR]

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development.

Background: The epidermal growth factor receptor (EGFR) has critical roles in signal transduction pathways, leading to cell growth and differentiation. EGFR expression levels vary among different breast tumor subtypes and ethnic groups. On the other hand, the relationship between EGFR expression at the mRNA level with clinicopathological characteristics in breast cancer has rarely been reported. Objectives: The present study focuses on the assessment of EGFR mRNA expression in breast tumors and the association of its expression with various clinicopathological features in Iranian patients with breast cancer. Methods: In this cross sectional study, the expression of EGFR was assessed by real time PCR technique in tumors of 52 Iranian women (27 luminal and 25 triple negative tumors) with primary breast cancer and 6 normal breast tissues. Results: The results of this study showed that EGFR mRNA was overexpressed only in triple negative tumors, and there is a high frequency of EGFR underexpression in luminal breast tumors, unlike triple negative tumors. We demonstrated that there is a significant positive correlation (r = 0.662) between EGFR expression and the size of luminal tumors. In the current study, the increased expression of EGFR is significantly associated with estrogen receptor (ER) negative, progesterone receptor (PR) negative, and grade III in breast tumors. Conclusions: These findings suggest that the majority of patients with triple negative tumors are likely eligible to receive the anti- EGFR therapies. Also, it seems that EGFR expression probably has an association withtumorsize in luminal subtype of breast tumors. [ABSTRACT FROM AUTHOR]

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Purpose:The aim of the study was to determine if the polymorphism rs2981582 exists in intron 2 of FGFR2 gene in Turkish breast cancer patients and to investigate the correlation between conventional clinicopathological features and gene polymorphism.Materials and Methods:Both normal and tumoral breast tissue samples were obtained from forty-eight breast cancer patients operated at Department of General Surgery, Ege University Hospital between 2008 and 2009 years. Samples were stored in stabilization solution (SABiosciences). DNA samples were isolated by using High Pure PCR Product purification kit (Roche, Mannheim, Germany). FGFR2 rs2981582 was identified by specific primer-probes (TıbMolBiol, Germany) and analysed with high resolution melting (HRM) analysis.Results:The genotypic distribution of the 48 patients for CC (wildtype), CT (heterozygote) ve TT (polymorphic) genotypes were found to be % 43,8 (n=21), %41,6 (n=20) and %14,6 (n=7), respectively. No difference was observed between normal and tumor tissue samples (p>0,05). Seven patients with polymorphic genotype (TT) showed immunohistochemically high estrogen receptor (ER) expression pattern and all of the polymorphic patients were luminal like subtype. Patients with wild-type genotype (CC) were more likely to have axillary metastases than the polymorphic (TT) group (U=36,5, p=0,043).Conclusion:This is the first study investigating the FGFR2 gene polymorphism in Turkish breast cancer patients. Further analysis of the relationship between slowly progressing luminal like subtype breast cancer and FGFR2 gene polymorphism might have implications for diagnosis or therapy of breast cancer.

Introduction: Germline mutations in BRCA1/2 are the most common cause of hereditary breast and ovarian cancer (HBOC) syndrome. Few studies published during the past decade reported the prevalence of germline BRCA mutations in Asian patients with breast cancer. We aimed to assess the prevalence and characteristics of Thai patients with breast cancer with germline BRCA1/2 mutations., Methods: We retrospectively reviewed all breast cancer patients who were tested for germline BRCA1/2 mutations during 2014-2018. BRCA mutations were detected using next-generation sequencing and confirmed using Sanger sequencing. We analyzed the characteristics of patients with or without BRCA mutations. Disease-free survival (DFS) and the associated factors were determined., Results: Among 67 patients, 12 (18%) were BRCA1/2 carriers (6 each), 4 (6%) harbored variants of uncertain significance, and 51 (76%) were non-carriers. We discovered two novel BRCA2 frameshift mutations (c.2380delA and c.8855dupT). Mean ages at breast cancer diagnosis of BRCA1, BRCA2, and non-carriers were 39.8, 46.2, and 42.0 years, respectively. The 12 tumors of BRCA carriers were mainly the luminal-B subtype. Two of these tumors were HER2-positive luminal-B, and the triple-negative subtype was not detected. After adjusting for stages and luminal subtypes, BRCA carriers experienced worse 3-year DFS than non-carriers (81.5% vs. 90.3%, HR 2.04 [0.64-6.49], p = .229). The stage at diagnosis was the sole factor significantly associated with 3-year DFS (100%, 84.8%, and 72.7%; stages I, II, and III, respectively)., Conclusion: Thai patients with breast cancer with BRCA1/2 mutations were mainly the luminal-B subtypes with worse prognosis than those without mutations., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Background: Indication for chemotherapy in estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers is determined on the basis of Ki67 expression level. However, since Ki67-high cancers are not necessarily sensitive to chemotherapy, identification of such patients who do not need chemotherapy is an important issue. Patients and methods: We used immunohistochemical staining to examine the expression levels of ER, progesterone receptor (PgR), Ki67, and geminin, a marker of S to G2/M phases, in 80 ER-positive/HER2-negative breast cancers. The labeling indices of Ki67 and geminin were determined and cutoff values were set at 15 and 6 %, respectively. Results: Ki67 and geminin expression levels were significantly associated with nuclear grade. In the Ki67-low subset, 26 out of 28 (92.9 %) cancers were geminin low and in the Ki67-high subset, 31 out of 52 (59.6 %) were geminin high. Distant disease-free survival (DDFS) of the geminin-high subset was significantly poorer than that of the geminin-low subset ( P = 0.009). In the Ki67-low subset, only one patient showed recurrence. Metastasis was detected in eight out of 31 (25.8 %) patients in the geminin-high group of the Ki67-high subset, but no recurrence was observed in the geminin-low group of the Ki67-high subset. Conclusion: Geminin-high breast cancers are significantly associated with worse prognosis. Since poorer prognosis was recognized only in the geminin-high group in Ki67-high cancers, we speculate that geminin may be useful for identifying patients in the Ki67-high subset who can avoid unnecessary chemotherapy. [ABSTRACT FROM AUTHOR]

Background: The Ki67 labeling index (LI) reflects the proliferative activity of breast cancers and defines luminal A and B tumors; however, no detailed method to measure Ki67 has been standardized. Here, we propose a fast and easy way to evaluate Ki67. Methods: Immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 (MIB-1) was performed on 235 primary invasive ductal carcinomas. For each sample, a hot spot with many Ki67+ cells was identified using a low-power field (40×, 4× objective). Three independent areas in high-power field (400×) were selected at the hot spot, and all cancer cells in the 3 areas were manually counted to calculate LI (% Ki67+ cells). Alternatively, micrographs taken at 100× and 200× fields including the hot spot were shown to 2 pathologists, who visually assessed percentages of Ki67+ cells in 10 % intervals at a glance (Eye-10). Results: Eye-10 and LI were strongly correlated ( r = 0.9412, P < 0.0001). All cases of Eye-10 ≥ 30 % had LI > 14 %; most of those <10 % had LI < 14 %. Of 170 ER+/HER2− tumors, Eye-10-based subtypes matched 87 % of LI-driven subtypes, and interobserver agreement was good ( κ = 0.705). Conclusion: Eye-10 is far easier than counting many cancer cells and useful for classifying breast cancers. Eye-10 can exclude obviously high and low Ki67 cases, leaving a 'gray zone' around a cutoff point. Combining Eye-10 and manual counting is a good candidate for a standard method to evaluate Ki67. [ABSTRACT FROM AUTHOR]

Background: The criteria for classifying hormone receptor (HR)-positive/HER2-negative breast cancers into low-risk and high-risk subgroups remain undetermined. Supportive data for optimal criteria to identify tumors in the high-risk subgroup are necessary for Japanese patients with HR-positive/HER2-negative breast cancers. Methods: Using immunohistochemistry and fluorescence in situ hybridization, we identified 369 consecutive patients with HR-positive/HER2-negative, node-negative invasive breast cancers. We examined the prognostic impact of the Ki-67 labeling index (LI) based on 3 cutoff values, 10, 14, and 20 %, along with that of histological grade (HG) and nuclear grade (NG) by Cox's univariate and multivariate analyses. Results: The univariate analyses clearly showed that Ki-67 LI with any cutoff value divided the patients into distinct high-risk and low-risk groups, and that HG and NG were also powerful prognostic indicators. High Ki-67 LI with any cutoff value was strongly correlated with HG and NG, and when these parameters were included in the multivariate analyses, the impact of HG/NG was stronger than Ki-67 LIs. When the 10 % cutoff value was adopted, discordance between Ki-67 LI and grades was frequent in papillotubular-type invasive ductal carcinoma, predominantly intraductal carcinoma, and mucinous carcinoma. Conclusions: Any of the Ki-67 LI values, regardless of cutoff value, could be applicable for the classification of high-risk and low-risk HR-positive/HER2-negative, node-negative invasive breast cancers. Luminal A/B subtyping according to Ki-67 LI, or HG/NG, in combination with histological type, appeared to be able to create an optimum risk estimation system for patients with HR-positive/HER2-negative, node-negative invasive breast cancers in Japan. [ABSTRACT FROM AUTHOR]

Bladder cancer is a heterogeneous disease, which exhibits a wide spectrum of clinical and pathologic features. Recent genomic studies have revealed that distinct molecular alterations may underlie the diverse clinical behaviors of bladder cancer, leading to a novel molecular classification. The intrinsic molecular subtypes exhibit distinct gene expression signatures and different clinicopathologic features. Genomic alterations also underlie the development of bladder cancer histologic subtypes. Genomic characterization provides new insights to understanding the biology of bladder cancer and improves the diagnosis and treatment of this complex disease. Biomarkers can aid the selection of patients for immune checkpoint therapy., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negetive breast cancers can be divided into luminal A and luminal B subtypes based on Ki67 expression levels. However, the biological differences in ER and progesterone receptor (PR) expression levels between these luminal subtypes are not clear. Methods: We examined immunohistochemical expression levels of ER, PR, and Ki67 in 180 ER-positive/HER2-negative breast cancers while taking menopausal status into account. Breast cancers were divided according to ER and PR levels (H: >50%, L: ≤50%), and luminal A and B were classified by the Ki67 labeling index (A: Ki67 <14%, B: Ki67 ≥14%). Results: When breast cancers were classified based on ER and PR levels, the distribution of pre- and postmenopausals was significantly different for luminal A ( P < 0.0001), but not for luminal B cancers. As for luminal A, ER-H/PR-L cancers were rare among premenopausals (8%), but frequent among postmenopausals (54%). Correlation between ER and PR levels among luminal A cancers was strong in premenopausals but weak in postmenopausals. Since crosstalk with growth factor signaling is unlikely in luminal A, we speculate that intratumoral estrogen insufficiency contributed to the characteristics of postmenopausal ER-H/PR-L cancers. Conclusion: We speculate that the biological characteristics of luminal A cancers are influenced by the estrogen environment, but its influence on luminal B cancers may be limited. We believe these considerations constitute useful information for a better understanding of the biology of ER-positive-HER2-negetive breast cancers. [ABSTRACT FROM AUTHOR]

Background: Whether PET scan maximum standard uptake value (SUVmax) could differentiate luminal A from luminal B and help predict the survival of metastatic breast cancer (MBC) patients with luminal subtype is still unknown and need to be investigated. Methods: 305 MBC patients with luminal subtypes were screened with PET/CT. Eligible patients were prospectively followed up. Results: In total, 134 patients were eligible for this study. SUVmax was significantly related to the number of metastatic sites and presence of visceral metastasis on univariate analysis. SUVmax could not effectively differentiate patients with luminal A from luminal B subtype. Although luminal subtype at diagnosis could predict the relapse-free interval, it could not predict progression-free survival (PFS) or overall survival (OS) after developing relapse. In contrast, SUVmax was predictive of both PFS and OS and this effect was maintained in multivariate COX regression model. Conclusions: SUVmax of MBC did not correlate with molecular subtypes of primary tumor. While molecular subtype may be a valuable prognostic factor at primary diagnosis of breast cancer, the SUVmax, rather than molecular subtype, does have a potential to predict independently in multivariate analysis for the PFS and OS in patients with metastatic disease of luminal subtype. [ABSTRACT FROM AUTHOR]

Germline mutations in BRCA1 were already linked to basal-like subtype of immunophenotypic molecular classification of breast cancer (BC). However, it is not known whether mutations in other BC susceptibility genes are associated with molecular subtypes of this cancer. We tested the hypothesis that distinct mutations in another BC susceptibility gene involved in DNA repair, i.e., CHEK2 may be associated with particular immunophenotypic molecular subtypes of this cancer. Two groups of patients: 1255 with BCs and 5496 healthy controls were genotyped for four CHEK2 mutations (I157T and three truncating mutations: 1100delC, IVS2 + 1G > A, del5395). BCs were tested by immunohistochemistry on tissue microarrays for ER, PR, HER-2, EGFR, and CK5/6 and were assigned to appropriate subtypes of immunophenotypic molecular classification. There was a significant association between CHEK2 mutations and the immunophenotypic molecular classification ( P = 0.004). CHEK2-associated cancers were predominantly luminal (108/117 = 92.3%). CHEK2-I157T variant was associated with the luminal A subtype ( P = 0.01), whereas CHEK2-truncating mutations were associated with the luminal B subtype ( P = 0.005). Comparing the prevalence of CHEK2 mutations in BC with controls revealed that carriers of an I157T variant had OR of 1.80 for luminal A subtype and carriers of truncating mutations had OR of 6.26 for luminal B subtype of BC. To our knowledge, this is the first study showing that specific mutations in the same susceptibility gene are associated with different immunophenotypic molecular subtypes of BC. This association represents independent evidence supporting the biological significance of immunophenotypic molecular classification of BC. [ABSTRACT FROM AUTHOR]

Purpose: Luminal subtype breast cancer is defined as oestrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancer. We detected the expression of ER-α, ER-β1 and ER-β2 in the tissue samples of invasive luminal subtype breast cancer patients, evaluated the correlations between these ER statuses and prognosis, and tried to clarify whether the status of ER-α isoforms provides clinically useful information further to what is already provided by the traditional ER-α/PR assay. Methods: The expression of ER-α, ER-β1 and ER-β2 in the paraffin-embedded sections of 162 invasive luminal subtype breast cancer patients was detected with an immunohistochemical staining method. With mid-long-term follow-up, the features of ER-α, ER-β1 and ER-β2 status and the correlations between clinical characteristics and the prognosis were analysed. Results: ER-β1-positive status was correlated with PR ( rs=0.217, p<0.01). The median follow-up time was 92 months (range, 4-98 months). Univariate analysis suggested that ER-β1 status was significantly correlated to diseasefree survival (DFS) time (log rank=3.98, p=0.046), especially in patients with positive lymph nodes (log rank=6.20, p=0.013). In patients with smaller tumour size (≤20 mm), negative ER-β2 status was significantly correlated to overall survival time (log rank=3.87, p=0.049). Conclusions: In invasive luminal subtype breast cancers, ER-β1 is correlated with good prognosis and could be regarded as one of the factors for evaluating DFS time, especially in lymph node-positive patients. There may be some interactions between ER-β1 and PR. In clinical practice, besides routine detection of ER-α and PR in invasive luminal subtype breast cancers, immunohistochemical staining of ER-β1 and ER-β2 should be considered in order to achieve more useful information. Further studies are needed to confirm our findings. [ABSTRACT FROM AUTHOR]

A pathological complete remission (pCR) is rarely achieved by neoadjuvant chemotherapy in estrogen receptor-positive (ER+) HER2-negative (HER2−) tumors. Therefore, its use might be questionable in specific groups of this tumor type. To select which patients benefit and which could be spared neoadjuvant chemotherapy, we tested standard pathology and molecular markers in ER+ HER2− breast tumors. Pretreatment biopsies were available from 211 ER+ HER2− tumors, who had been treated with neoadjuvant chemotherapy (adriamycin/cyclophosphamide). mRNA expression data were available for 132 tumors. We determined progesterone receptor expression (PR), endocrine sensitivity, HER2 expression, histology, proliferation, and molecular subtypes. We correlated these data to chemotherapy response using pCR rates and the previously published neoadjuvant response index (NRI). PR-negative tumors ( n = 65, 30.8%) and luminal B type tumors ( n = 43, 20.4%) responded significantly better to chemotherapy than other tumors. These associations remained significant in multivariate analysis. However, even in the subgroup of patients with the lowest response rate, comprising tumors that had both a positive-PR expression and the luminal A subtype ( n = 58, 44%), the majority of the patients had downstaging because of chemotherapy. For histology (lobular vs. ductal), endocrine sensitivity, and proliferation, no associations with chemotherapy response were observed. Gene expression array analysis resulted in 28 significant genes (FDR < 0.1). PR expression and luminal B status are associated with a better response to neoadjuvant chemotherapy. However, both markers had only weak response predictive power, and it was not possible to identify a subgroup with no or only minimal chemotherapy benefit. Therefore, the decision to refrain from neoadjuvant chemotherapy to ER+ HER2− breast tumors should not be based on predictive markers, but exclusively on estimates of prognosis. [ABSTRACT FROM AUTHOR]

Objective: Breast cancer cells with CD44+CD24-/low gene expression signature have been suggested to have stem cell-like tumor-initiating properties. The purpose of this study is to clarify the gene expression profiling of cells with CD44+CD24-/low gene expression signature in the luminal subtype. Methods: Laser capture microdissection was used to select the isolation of cancer cells in 35 frozen tissues of breast cancer, and RNA extracted from these cells was examined by real-time RT-PCR to quantify CD44 and CD24 expressions. Human stem cell RT2 Profiler PCR Array was used for gene expression analysis in the groups of CD44+CD24-/low and CD44+CD24+ gene expression signature. Results: Thirty-five tumors were divided into 3 groups. Group A was composed of the CD44+CD24-/low type, in which the ratio of CD44/CD24 was >10.0. Group B was composed of the CD44+CD24+ type, in which the ratio was >0.1 and ≤10.0. In group C, composed of the CD44-/lowCD24+ type, the ratio was <0.1. The number of tumors in groups A, B, and C were 5, 28, and 2, respectively. Regarding the correlation of CD44/CD24 status with tumor characteristics, the tumors of group A were significantly associated with axillary lymph node metastasis compared with those of group B (p = 0.033). There were no significant differences in tumor size, nuclear grade, or HER2 status between the two groups. According to signaling pathways, the number of expression genes for the Notch pathway in group A was significantly greater than in group B (p = 0.028). Overexpressed genes for ALDH1 (p = 0.021) and SOX2 (p = 0.018) were noted in group A compared to group B. Conclusion: This study suggests that the Notch pathway may be an important signaling pathway in luminal subtype with CD44+CD24-/low gene expression signature. In addition, either ALDH1 or SOX2 may be a candidate marker for cancer stem cells in luminal subtype breast cancer. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to determine if the polymorphism rs2981582 exists in intron 2 of FGFR2 gene in Turkish breast cancer patients and to investigate the correlation between conventional clinicopathological features and gene polymorphism. Materials and Methods: Both normal and tumoral breast tissue samples were obtained from forty-eight breast cancer patients operated at Department of General Surgery, Ege University Hospital between 2008 and 2009 years. Samples were stored in stabilization solution (SABiosciences). DNA samples were isolated by using High Pure PCR Product purification kit (Roche, Mannheim, Germany). FGFR2 rs2981582 was identified by specific primer-probes (TibMolBiol, Germany) and analysed with high resolution melting (HRM) analysis. Results: The genotypic distribution of the 48 patients for CC (wildtype), CT (heterozygote) ve TT (polymorphic) genotypes were found to be % 43,8 (n=21), %41,6 (n=20) and %14,6 (n=7), respectively. No difference was observed between normal and tumor tissue samples (p>0,05). Seven patients with polymorphic genotype (TT) showed immunohistochemically high estrogen receptor (ER) expression pattern and all of the polymorphic patients were luminal like subtype. Patients with wild-type genotype (CC) were more likely to have axillary metastases than the polymorphic (TT) group (U=36,5, p=0,043). Conclusion: This is the first study investigating the FGFR2 gene polymorphism in Turkish breast cancer patients. Further analysis of the relationship between slowly progressing luminal like subtype breast cancer and FGFR2 gene polymorphism might have implications for diagnosis or therapy of breast cancer. [ABSTRACT FROM AUTHOR]

Background: Axillary lymph node involvement remains the most important prognostic factor in early-stage breast cancer. We hypothesized that molecular classification based on breast cancer biology would predict the presence of nodal involvement at diagnosis, which might aid treatment decisions regarding the axilla. Patients and Methods: From a clinically annotated tissue microarray of 4444 early-stage breast cancers, expression of estrogen receptor (ER), progesterone receptor (PgR), HER2, epidermal growth factor receptor, and cytokeratin 5/6 was determined by immunohistochemistry. Cases were classified by published criteria into molecular subtypes of luminal, luminal/HER2 positive, HER2 positive/ER negative/PgR negative, and basal. Risk of axillary nodal involvement at diagnosis was determined in 2 multivariable logistic regression models: a "core biopsy model" including molecular subtype, age, grade, and tumor size and a "lumpectomy model," which also included lymphovascular invasion. Luminal was used as the reference group. After internal validation of findings in 2 independent sets, we conducted combined analysis of both. Results: In the core biopsy model, the molecular subtypes had a predictive effect for nodal involvement (P = .000001), with the basal subtype having an odds ratio for axillary lymph node involvement of 0.53 (95% CI, 0.41-0.69). Tumor grade (P = 5.43 × 10–12) and size (P = 8.52 × 10–35) were also predictive for nodal involvement. Similar results were found in the lumpectomy model, where lymphovascular invasion was also predictive (P = 2.74 × 10–115). Conclusion: These results indicate that the basal breast cancer molecular subtype predicts a lower incidence of axillary nodal involvement, and including biomarker profiles to predict nodal status at diagnosis could help stratification for decisions regarding axillary surgery and locoregional radiation. [ABSTRACT FROM AUTHOR]

With improved survival, more patients with prior breast cancer are at risk of having a second primary cancer diagnosed. The pattern and impact of second primary cancers following breast cancer is important for overall breast cancer therapeutic management. Our study is a first analysis of the trend of second primary tumours over time in terms of incidence, sites with significantly elevated risks and correlation with stage, molecular subtype and therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. Patients and methods: Our study population included 28 patients with prior breast cancer (BC) and second primary tumours, which were diagnosed and treated in our Institution between 2004 and 2017. The criteria for selection were based on the completeness of the documentation of the first treatment for breast cancer, stage of disease, molecular subtype, the site of origin of the second tumours and the survival data. Results: An increased risk of second primary cancer was associated with the 51–60 years age group (53.6%), with the greater prevalence in patients living in urban environments (82.1%). The use of chemotherapy increased the risk of the occurrence of gynecological second malignancies (75%). Our study is a first analysis of the trend of second primary tumours over time in terms of identifying sites with significantly elevated risks and correlation with therapeutic strategies conducted in Eastern Europe in postmenopausal women with breast cancer. Conclusions: Our study is a first analysis of the trend of second primary tumours over time in terms of correlation with luminal subtype and stage at diagnosis of primary cancer sites with significantly elevated risks and correlation with therapeutic strategies in postmenopausal women with breast cancer conducted in Eastern Europe. The reported time from primary to second primary malignancy onset, with a significantly higher rate for postmenopausal breast cancer patients, was less than one year (50%). With the advances and wider availability of genetic testing (e.g., gene panels), patients diagnosed with multiple primaries should be increasingly investigated for an underlying cancer predisposition. Postmenopausal women with breast cancer may benefit from increased surveillance and advice to avoid second malignancies. [ABSTRACT FROM AUTHOR]