Estrogen Receptor Negative Research Articles

Prognostic implications of the expression levels of different immunoglobulin heavy chain-encoding RNAs in early breast cancer

The extent and composition of the immune response in a breast cancer is one important prognostic factor for the disease. The aim of the current work was to refine the analysis of the humoral component of an immune response in breast tumors by quantifying mRNA expression of different immunoglobulin classes and study their association with prognosis. We used RNA-Seq data from two local population-based breast cancer cohorts to determine the expression of IGJ and immunoglobulin heavy (IGH) chain-encoding RNAs. The association with prognosis was investigated and public data sets were used to corroborate the findings. Except for IGHE and IGHD, mRNAs encoding heavy chains were generally detected at substantial levels and correlated with other immune-related genes. High IGHG1 mRNA was associated with factors related to poor prognosis such as estrogen receptor negativity, HER2 amplification, and high grade, whereas high IGHA2 mRNA levels were primarily associated with lower age at diagnosis. High IGHA2 and IGJ mRNA levels were associated with a more favorable prognosis both in univariable and multivariable Cox models. When adjusting for other prognostic factors, high IGHG1 mRNA levels were positively associated with improved prognosis. To our knowledge, these results are the first to demonstrate that expression of individual Ig class types has prognostic implications in breast cancer.

Leg Injury - Football

HISTORY: A 12-year old male quarterback sustained a right leg injury while cutting back across the field. He was running across the field and made a lateral cut to change directions, as this happened he tripped over himself and fell without a twisting motion. He landed on his right lateral leg with immediate pain to the fibular head. There was no numbness, tingling, weakness or radiation of pain however he had a noticeable limp. He presented to clinic 2 days later and denied any prior injuries or trauma to the area. PHYSICAL EXAMINATION:2 days post injury (PCP office) — No deformity, normal knee and ankle exams, no bony tenderness, moderate postero-lateral edema of proximal right lower leg, painful/antalgic gait, TTP lateral gastrocnemius and soleus, negative Thompson's.4 days post injury (Sports Medicine Clinic) — Consistent with prior exam, new findings: point TTP just distal to fibular head, decreased edema, negative squeeze test, negative ER test. DIFFERENTIAL DIAGNOSIS: 1. R fibular contusion 2. R knee apophysitis 3. LCL sprain 4. Gastrocnemius contusion/strain 5. Distal Bicep Femoris strain TEST AND RESULTS: XR: R Tib/Fib AP and Lateral radiographs 2 days after injury — Bones/joints/soft tissue appear unremarkable. Repeat XR 13 days post injury — subtle irregularity along the lateral aspect of the proximal fibula physis with associated periostitis. Final XR 20 days post injury — Noted irregularity along the lateral aspect of the proximal fibula physis with increased benign periostitis. FINAL WORKING DIAGNOSIS: Salter-Harris II fracture of R proximal fibula physis TREATMENT AND OUTCOMES: 1. Cam walker boot 3 weeks with weekly exams/XRs 2. 20 days out from injury completely normal RLE exam, no pain, full ROM, XRs suggestive for healing SH2 fracture; patient was able to return to football as tolerated. DISCUSSION: In isolation this is a very rare injury. There was one reported case of a SH-3 fracture that presented with initial knee injury and ROM deficits that was treated non-operatively. Most injuries to the proximal physis of the fibula occur in combination with an interosseous membrane/syndesmotic and distal tibiofibular injury - must rule out a Maisonneuve injury. The presenting complaint was pain and edema in the region of the soleus this may have been a soleus traction injury to the apophysis vs direct trauma from the fall.

Incidence and Predictors of Recurrence among Breast Cancer Patients in Black Lion Specialized Hospital Adult Oncology Unit, Addis Ababa, Ethiopia: Retrospective Follow-up Study with Survival Analysis.

Currently, breast cancer is becoming a major public health problem for developing countries. In Ethiopia, breast cancer is the most prevalent cancer among women, and constitutes a major public health concern. Hence, this study was aimed to determine the incidence and predictor of recurrence among breast cancer clients at Black Lion Specialized Hospital, Ethiopia, in 2018. We analyzed 513 patients out of 835 women breast cancer patients treated at Black Lion Specialized Hospital. Recurrent-free survival was determined using the Kaplan–Meier method, with comparisons between groups through the log-rank test. The Cox proportional hazards model was used to identify predictors of recurrence among breast cancer clients. The incidence rate of recurrence among breast cancer was 6.5% per (95% CI = 6.49-12.47) follow-up. The median recurrent-free survival time was 60.33 months (95% CI = 54.46-62.30). Predictors of recurrence were negative estrogen receptor (hazard ratio [HR] = 1.8, 95% CI = 1.53-7.62), high histologic grade (HR = 2.8, 95% CI = 1.14-10.31), positive lymph node status (HR = 2.6, 95% CI = 1.14-10.31), clinical staging III (HR = 2.5, 95% CI = 1.26-9.42), and involved deep surgical margin (HR = 3.6, 95% CI = 2.14-8.61). This research showed that incidence of recurrence was high. Advanced clinical stage, positive nodal status, high histologic grade, negative estrogen receptor, and involved deep surgical margin were associated with higher recurrence rates. In contrast, hormonal therapy has a great role in decreasing the development of recurrence.

Clinicopathologic Characteristics of Breast Cancer According to the Infiltrating Immune Cell Subtypes.

The clinical significance of immune cell subtypes in breast cancer remains poorly understood. To identify tumor-infiltrating immune cell subtypes in breast cancer and investigate their implications, tissue microarrays were constructed using 334 cases of invasive ductal carcinoma (luminal A type: 162 (48.5%), luminal B type: 96 (28.7%), HER-2 type: 21 (6.3%), and triple negative breast cancer: 55 (16.5%)). Hormone receptors (ER, PR, and HER-2), Ki-67, and immune cell subtype-related proteins (STAT4, STAT6, FOXP3, CD8, CD68, and CD163) were assessed immunohistochemically. The proportion of highly expressed STAT6, FOXP3, CD8, CD68, and CD163 proteins was found to be lowest in luminal A type but highest in the HER-2 type. Additionally, high-level STAT6, FOXP3, CD68, and CD163 protein expression was associated with higher histologic grade. ER negativity was associated with high STAT6, FOXP3, and CD163 expression levels, whereas PR negativity and high Ki-67 labeling index were associated with high CD163 expression. Univariate (p = 0.003) and multivariate Cox (hazard ratio: 2.435, 95% CI: 1.110-5.344, p = 0.049) analyses showed that high CD8 expression is an independent factor associated with shorter disease-free survival. Immune cell subtype-related protein expression is dependent on breast cancer molecular subtypes, and CD8 expression is associated with patient prognosis.

The expression of calpain-1 and androgen receptor in breast cancer and their correlation with clinicopathological characteristics: An immunohistochemical retrospective study

Breast cancer is a heterogeneous disease with different biological outcome and ability to acquire resistance to therapy. The calpain family of proteases and androgen receptor (AR) are implicated in breast cancer pathogenesis and progression and are potential targets for novel treatment regimens. The aim of this study was to investigate the expression of calpain-1 and AR in breast cancer and to correlate their expression with clinicopathological variables and prognosis of patients.In this study we enrolled 219 breast cancer patients with long term follow-up information available. Immunohistochemical methods on a tissue microarray were used to investigate expression of calpain-1 and AR in tumor cells.The expression of calpain-1 and AR both differed significantly between the tumor subtypes of patients (p = 0.002 and p = 0.042 respectively). High calpain-1 expression was associated with patient’s age over 50 years (p = 0.005) and positive ER status (p = 0.009), but not with other clinicopathological variables. Women with AR negative breast cancers were more likely to be older (p = 0.016), to have bigger tumors (p = 0.032), higher stage of the disease (p = 0.026), presence of exulceration (p = 0.017), negative ER status (p = 0.007) and higher Ki-67 proliferative index (p = 0.027). Calpain-1 expression was not associated with breast cancer specific overall survival in the total cohort of patients, however low calpain-1 expression was associated with adverse survival (p = 0.018) in triple negative subgroup of patients. Low calpain-1 expression was also associated with significantly shorter 5-year disease-free survival in total cohort of patients (p = 0.03). AR status was not associated with overall and disease-free survival of patients.This study has demonstrated that the expression of calpain-1 and androgen receptors are associated with important clinicopathological variables. The expression of calpain-1 was associated with improved disease-free survival of all analyzed patients and with improved overall survival of triple negative breast cancer patients.

Effects of tumor-specific CAP1 expression and body constitution on clinical outcomes in patients with early breast cancer

BackgroundObesity induces molecular changes that may favor tumor progression and metastatic spread, leading to impaired survival outcomes in breast cancer. Adenylate cyclase-associated protein 1 (CAP1), an actin regulatory protein and functional receptor for the obesity-associated adipokine resistin, has been implicated with inferior cancer prognosis. Here, the objective was to investigate the interplay between body composition and CAP1 tumor expression regarding breast cancer outcome through long-term survival analyses.MethodsAmong 718 women with primary invasive breast cancer within the large population-based prospective Malmö Diet and Cancer Study, tumor-specific CAP1 levels were assessed following thorough antibody validation and immunohistochemical staining of tumor tissue microarrays. Antibody specificity and functional application validity were determined by CAP1 gene silencing, qRT-PCR, Western immunoblotting, and cell microarray immunostaining. Kaplan-Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of breast cancer-specific survival (BCSS) and overall survival (OS) according to body composition and CAP1 expression.ResultsStudy participants were followed for up to 25 years (median 10.9 years), during which 239 deaths were observed. Patients with low CAP1 tumor expression were older at diagnosis, displayed anthropometric measurements indicating a higher adiposity status (wider waist and hip, higher body mass index and body fat percentage), and were more prone to have unfavorable tumor characteristics (higher histological grade, higher Ki67, and estrogen receptor (ER) negativity). Overall, patients with CAP1-low tumors had impaired BCSS (adjusted hazard ratio: HRadj = 0.52, 95% CI 0.31–0.88) and OS (HRadj = 0.64, 95% CI 0.44–0.92) compared with patients having high CAP1 tumor expression. Further, analyses stratified according to different anthropometric measures or ER status showed that the CAP1-associated survival outcomes were most pronounced among patients with low adiposity status or ER-positive disease.ConclusionsLow CAP1 tumor expression was associated with higher body fatness and worse survival outcomes in breast cancer patients with effect modification by adiposity and ER status. CAP1 could be a novel marker for poorer survival outcome in leaner or ER-positive breast cancer patients, highlighting the need for considering body constitution in clinical decision making.

Abstract C087: Differences in estrogen receptor-negative breast cancer by race and SEER registry

Abstract Background: Estrogen receptor-negative (ERN) breast cancer is an early-stage, more aggressive breast cancer subtype. ERN breast cancer incidence is highest in African American women compared with other races, as well as in southern US regions. However, recent studies have shown that ERN breast cancer incidence is declining for women overall. We sought to understand whether ERN breast cancer is declining similarly in all races, age groups, and SEER registries. Methods: Data from Surveillance, Epidemiology, and End-Results (SEER) Program 13 registries from 1990-2014, as well as the remaining five SEER 18 registries from 2000-2014, were used to observe ERN breast cancer incidence rates among non-Hispanic white (NHW) and non-Hispanic black (NHB) women by age group (30-39, 40-49, 50-69, 70-84 years). Age-period-cohort modeling was used and extended, allowing for regional heterogeneity by population (i.e. SEER registry), to estimate differences in longitudinal age trends and net drifts by race and SEER registry. Results: Among all age groups within all SEER 18 registries, ERN breast cancer incidence rates were higher for NHB compared to NHW women. Furthermore, ERN rates have been decreasing for both NHW and NHB women. For the entire SEER population, women ages 40-49 years compared to other age groups demonstrated the fastest declines in ERN breast cancer incidence, with a net drift of -3.5%/year (95% CI: -4.0, -3.1) for NHW women, and -3.1%/year (-3.8, -2.2) for NHB women. Among the youngest women (30-39 years), ERN rates have declined faster in NHB compared to NHW women, with net drifts of -2.7%/year (-3.5, -1.8) and -1.7%/year (-2.2, -1.2), respectively; for all other age groups, rates have declined faster for NHW compared to NHB women. For NHW women of all age groups, there was relatively little between-registry variability in trends, with net drift standard deviations of 0.5%/year (0.02, 1.3) for 30-39 years, 0.8%/year (0.4, 1.2) for 40-49 years, 0.6%/year (0.4, 0.9) for 50-69 years, and 0.7%/year (0.4, 1.1) for 70-84 years. For NHB women, rates have also decreased similarly across registries in the youngest age group (30-39 years), with between-registry net drift standard deviation of 0.4%/year (0.01, 1.5); however, for NHB of all other age groups, there was more between-registry variability with net drift standard deviations of 1.0%/year (0.1, 2.1) for 40-49 years, 1.0%/year (0.4, 1.8) for 50-59 years, and 1.2%/year (0.4, 2.4) for 70-84 years. These standard deviations reflect that ERN rates have been declining more slowly in southern registries (i.e., Greater Georgia, Atlanta, Rural Georgia, and Louisiana) for older NHB women. Conclusion: Among NHW women, decreases in ERN breast cancer incidence have been similar across age groups and SEER registries. Among NHB women, ERN rates have also been decreasing; however, these decreases vary by age and SEER registry, which may offer etiologic clues. Further investigation is needed to understand which factors are contributing to these trends. Citation Format: Brittny C. Davis Lynn, Pavel Chernyavskiy, William F. Anderson, Gretchen L. Gierach, Philip S. Rosenberg. Differences in estrogen receptor-negative breast cancer by race and SEER registry [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C087.

Correlation between peripheral blood inflammatory indicators and pathologic complete response to neoadjuvant chemotherapy in locally advanced breast cancer patients.

The immune system plays a fundamental role in the response to neoadjuvant chemotherapy (NAC) of locally advanced breast cancer (LABC) patients. Patients with pathological complete response (pCR) after NAC have a higher survival rate. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are peripheral blood indicators of inflammatory response. This investigates the correlation between NLR, PLR, LMR, and other clinicopathological features of breast cancer patients before receiving NAC and pCR.Data of LABC patients who underwent NAC between 2009 and 2018 were retrospectively reviewed. Each patient's peripheral complete blood count was recorded before starting NAC. The cut-off values for neutrophils, lymphocytes, monocytes, and platelets in the peripheral blood and NLR, PLR, and LMR were determined by receiver operating characteristic curve analyses.The records of 131 patients were analyzed and divided into two groups, pCR (+ve) and pCR (-ve), and their clinicopathological features and laboratory findings were compared. pCR was achieved in 23.6% of patients. The cut-off values of neutrophils, lymphocytes, monocytes, and platelets at the time of diagnosis and NLR, PLR, and LMR were, respectively, 4150 μL, 2000 μL, 635 μL, 271 × 10 μL, 1.95, 119, and 3.35. The pCR rate was higher in patients with low neutrophil count, low NLR, and high lymphocyte count (P = .002, <.001, and .040, respectively).As per the findings of multivariate logistic regression analysis, the independent predictive factors of pCR were clinical tumor size T1 and T2, grade 3, ER negativity, and low NLR (P = .015, .001, .020, .022, and .001, respectively).While NLR was found to be an independent predictive factor of pCR in LABC patients receiving NAC, a similar result was not observed for PLR and LMR. NLR can be a useful biomarker for predicting the response of patients receiving NAC.

Detection of ctDNA with Personalized Molecular Barcode NGS and Its Clinical Significance in Patients with Early Breast Cancer

We attempted to detect circulating tumor DNA (ctDNA), taking advantage of molecular barcode next-generation sequencing (MB-NGS), which can be more easily customized to detect a variety of mutations with a high sensitivity than PCR-based methods. Sequencing with a gene panel consisting of the 13 most frequently mutated genes in breast tumors from stage I or II patients revealed 95 somatic mutations in the 12 genes in 62% (62/100) of tumors. Then, plasma DNA from each patient (n = 62) before surgery was analyzed via MB-NGS customized to each somatic mutation, resulting in the detection of ctDNA in 16.1% (10/62) of patients. ctDNA was significantly associated with biologically aggressive phenotypes, including large tumor size (P = .004), positive lymph node (P = .009), high histological grade (P < .001), negative ER (P = .018), negative PR (P = .017), and positive HER2 (P = .046). Furthermore, distant disease-free survival was significantly worse in patients with ctDNA (n = 10) than those without ctDNA (n = 52) (P < .001). Our results demonstrate that MB-NGS personalized to each mutation can detect ctDNA with a high sensitivity in early breast cancer patients at diagnosis, and it seems to have a potential to serve as a clinically useful tumor marker for predicting their prognosis.

High-risk of recurrence for nodal micrometastasis with breast pathologic complete response (ypT0/Tis ypN1mi) after neoadjuvant chemotherapy.

e12524 Background: Nodal micrometastatic disease (ypN1mic) after neoadjuvant chemotherapy (nCT) for breast cancer (BC) is considered an indication for axillary lymph node disection. While pN1mic prognostic impact has been extensively studied, the prognostic impact of ypN1mic disease is uncertain and these patients are usually grouped together with nodal macrometastatic disease. Since outcomes may be difficult to evaluate in the setting of BC residual disease, our aim was to compare the prognostic meaning of ypN1mic with that of ypN0 when a pCR is obtained in the breast. Methods: We retrospectively analyzed a series of 454 BC consecutive patients treated between 2010 and 2018 with neoadjuvant chemotherapy (nCT) based on anthracyclines and taxanes (plus antiHER2 treatment when appropriate). Pathologic complete response (pCR) was defined as ypT0/Tis ypN0. Patients with pre-nCT sentinel lymph node biopsy or without post-nCT pathologic evaluation were excluded. Disease free (DFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox regression models. Results: 454 BC patients were included, with 106 (24%) pCR. Median follow-up was 39 months. 99 (21.8%) patients obtained a pCR both in breast and axilla (ypT0/Tis ypN0), with 4 recurrences (4%) while only 7 (1.5%) patients had isolated nodal micrometastatic disease (ypT0/Tis ypN1mic), with 2 recurrences (28%). Median DFS was not reached for the ypN0 group and was 28 months (95%CI: 21.6-34.4 months) for the ypN1mic group (HR: 16.55, 95%cI: 2.68-102.37; p = 0.003). No differences were observed for OS (p = 0.77), although 2/2 ypN1mi showed distant recurrence (2/4 for ypN0 patients). Baseline clinical and pathologic characteristics were comparable between both groups, with no differences in performance status (p = 0.45), clinical nodal stage (p = 0.48), HER2 (p = 0.32), estrogen receptors (p = 0.93), grade (p = 0.34), presence of carcinoma in situ (0.60) or clinical complete response (p = 0.42). Clinical characteristics of patients with recurrence were also similar (100%: clinically positive nodes, negative estrogen receptors, no clinical complete response). Conclusions: Residual nodal micrometastatic disease after nCT seems to be associated with a higher risk of recurrence. Although longer follow-up and larger series are needed to confirm our data, these results support the escalation of post-nCT treatment even in patients with ypN1mic and breast pCR.

Simple Peripheral Blood Cell Parameters: Neutrophil/Lymphocyte, Platelet/Lymphocyte and Monocyte/Lymphocyte Ratios Do Not Determine Breast Cancer Subtypes

Breast cancer is associated with different intrinsic biological subtypes, depending on immunohistochemical properties and gene expression patterns, and these subtypes play a determinant role in the treatment approach and clinical results. In the current study, the neutrophil–lymphocyte, platelet–lymphocyte and monocyte–lymphocyte ratios were evaluated as potential prognostic indicators of breast cancer types and subtypes. A retrospective evaluation of 243 patients was performed. Breast cancer subtypes were classified as luminal A, luminal B, HER2 and triple-negative subtypes. The luminal A subtype was ER positive and/or PR positive and HER2 negative and Ki-67 low. The luminal B subtype was ER positive and/or PR positive or negative and HER2 negative and Ki-67 high or ER positive and/or PR positive or negative and HER2 positive and any Ki-67. The HER2 subtype was ER and PR negative and HER2 positive. The triple-negative subtype was ER negative, PR negative and HER2 negative. Full blood count results were obtained before surgery, and the NLR, PLR and LMR values in breast cancer patients with different molecular subtypes were calculated. There was no significant difference between the NLR, LMR and PLR according to the breast cancer subtypes (luminal A, luminal B, HER2 and triple negative) (p = 0.83, p = 0.34 and p = 0.20). The present study found no significant correlation between pre-operative NLR, PLR and LMR values and tumour subtypes.

Higher densities of tumour-infiltrating lymphocytes and CD4+ T cells predict recurrence and progression of ductal carcinoma in situ of the breast.

Host immunity influences cancer progression and therapeutic response. We investigated the potential of tumour-infiltrating lymphocytes (TILs) around ductal carcinoma in situ (DCIS) in predicting recurrence and progression. CD4, CD8, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in DCIS from 198 patients was determined by immunohistochemistry. We correlated disease-free survival (DFS), clinicopathological parameters and biomarker expression with TIL density and CD4/CD8 ratio. High TIL density was associated with high nuclear grade (P<0.001), DCIS PD-L1 expression (P=0.008), TIL PD-L1 expression (P<0.001), oestrogen (ER) negativity (P<0.001), progesterone (PR) negativity (P<0.001), human epidermal growth factor receptor 2 (HER2) positivity (P=0.002) and triple negativity (P=0.001). TIL PD-L1 expression was associated with triple-negative DCIS (P=0.028). TIL density was associated with molecular subtypes (P<0.001). High CD4+ T cell density was associated with high nuclear grade (P=0.001), microinvasion (P=0.037), ER negativity (P<0.001), PR negativity (P=0.001), HER2 positivity (P=0.004), triple negativity (P=0.023) and PD-L1 expression in TILs (P<0.011). High CD4/CD8 ratio was associated with PD-L1 expression in DCIS (P=0.035) and TILs (P<0.001). DCIS with higher TIL density disclosed worse DFS (P=0.012) and was affirmed with multivariate analysis [95% confidence interval (CI)=1.109-2.554, hazard ratio (HR)=1.683, P=0.014]. Poorer DFS for ipsilateral invasive recurrence was found for DCIS with higher CD4+ T cell density (P=0.006) or CD4/CD8 ratio (P=0.02), confirmed by multivariate analysis for the former (95% CI=1.369-10.196, HR=3.736, P=0.01) and latter (95% CI=1.311-7.935, HR=3.225, P=0.011). DCIS with higher TIL density was associated with poorer prognostic parameters and predicted recurrence, while both CD4+ T cell density and CD4/CD8 ratio were associated with both recurrence and ipsilateral invasive recurrence.

Radiological audit of interval breast cancers: Estimation of tumour growth rates

IntroductionThis multicentre, retrospective study aimed to establish correlation between estimated tumour volume doubling times (TVDT) from a series of interval breast cancers with their clinicopathological features. The potential impact of delayed diagnosis on prognosis was also explored. Materials and methodsInterval cancers, where screening mammograms demonstrated changes that were retrospectively classified as either uncertain or suspicious, were reviewed from five screening units within the UK NHS Breast Screening Programme (NHSBSP). Data collected included the time interval between screening mammogram and cancer diagnosis, the size of the initial mammographic abnormality and of the subsequent cancer, demographics, mammographic density and tumour biology. We estimated volume doubling times and the estimated change in size and node status, which would have followed if these cancers had been detected at the previous screen. Results306 interval cancers meeting the inclusion criteria were identified. Average time from screening to diagnosis was 644 days (SD 276 days). 19% were diagnosed in the first twelve months, 42% in the subsequent twelve months and 39% thereafter. Overall average estimated TVDT was 167 days (95% CI 151–186). Significant differences were noted with age (p = 0.01), grade (p < 0.001) and ER status (p < 0.001) with women under 60, grade 3 cancers and ER negative cancers having shorter TVDTs. HER2 positive tumours had shorter doubling times than HER2 negative, but this difference was not statistically significant. It was estimated that diagnosing these cancers at the previous screen would have increased ten-year survival from 82% to 86%. ConclusionHigh grade, ER negativity and younger age were associated with shorter durations of TVDT. The role of HER2 status on interval cancer growth rate requires further assessment. It is likely that the delayed diagnosis of interval cancers confers a 4% reduction in ten-year survival.

Immunohistochemical Expression of BRCA1 Protein, ER, PR and Her2/neu in Breast Cancer: A Clinicopathological Study.

Breast cancer is a heterogeneous hormone-dependent disease. Potential prognosis depends on the clinicopathological evaluation and assessment of other prognostic indicators. The detection of the oestrogen Receptor (ER), Progesterone Receptor (PR), Human epidermal growth factor receptor 2 (Her2/neu) and BRCA1 oncoprotein is pivotal for prognostic evaluation and to choose the appropriate post-surgical adjuvant therapy beside selecting the proper candidate for genetic counselling. Objectives:To detect the immunoexpression of the BRCA1 oncoprotein in mammary invasive ducal carcinoma and its association with the prognostic markers (ER, PR and Her2/neu hormonal receptors) and other clinicopathological parameters to improve the patients’ treatment plans. Methods:A cross-sectional study design including 83 paraffin blocks and histological slides collected from Al-Jumhoori Medical City Teaching Hospital Laboratory in Mosul and the Central Public Health Laboratory in Baghdad between the 1st of January 2010 to the 13th of March 2012 for patients diagnosed with primary invasive ductal breast carcinomas. Immunohistochemistry (IHC) using monoclonal antibodies against ER, PR, Her2/neu receptors and BRCA1 protein was performed via the fully automated immunostaining instrument ‘Ventana Benchmark’. Results:BRCA1 protein immunoexpression was detected in 20.5% of cases. It was significantly high with increasing tumour grade and stage. Although there was a trend of BRCA1 negativity toward negative ER, PR and Her2 receptors, no significant associations were observed with any of these parameters and the patients’ age. Conclusion:Altered BRCA1 expression is significantly associated with advanced tumour grade and stage. High number of cases with negative BRCA1 expression showed negative ER, PR and Her2/neu expression.

Clinicopathological and prognostic value of hypoxia-inducible factor-1α in breast cancer: a meta-analysis including 5177 patients.

Mounting studies have investigated the clinicopathological and prognostic value of hypoxia-inducible factor-1α (HIF-1α) in breast cancer (BC), yet conclusions remain controversial. Therefore, we conducted this meta-analysis to clarify this issue. All relevant studies were searched using Cochrane Library, Web of Science, PubMed, and EMBASE online databases. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the clinicopathological and prognostic value of HIF-1α, respectively. Subgroup analysis and sensitivity analysis were performed to investigate heterogeneity and stability of the results. Begg's funnel plot and Egger's test were used to examine publication bias. A total of 31 eligible studies including 5177 subjects were enrolled. Of these, 25 studies assessed the prognostic role of HIF-1α and included 4546 individuals. Twenty-three studies involving 3277 individuals evaluated the clinicopathological significance of HIF-1α. High expression level of HIF-1α was correlated with poor overall survival (OS) (HR = 1.59, 95% CI = 1.40-1.80, P < 0.001), disease-free survival (DFS) (HR = 1.87, 95% CI = 1.53-2.28, P < 0.001), relapse-free survival (HR = 1.36, 95% CI = 1.07-1.73, P = 0.001), and cancer-specific survival (HR = 1.55, 95% CI = 1.10-2.19, P = 0.012). Pooled data from studies using multivariate survival analysis also showed that HIF-1α expression was associated with worse OS (HR = 1.59, 95% CI = 1.32-1.92, P < 0.001) and DFS (HR = 1.60, 95% CI = 1.39-1.84, P < 0.001). Additionally, high HIF-1α expression was associated with advanced tumor-node-metastasis stage, positive lymph-node status, negative ER status, ductal type, advanced histologic grade, high Ki67 expression, and strong VEGF expression. HIF-1α might serve as an independent prognostic biomarker and a promising therapeutic target for BC. Future large-scale prospective randomized trials are needed to confirm our findings.

Clinico-pathologic features, treatment and outcomes of breast cancer during pregnancy or the post-partum period.

Breast cancer during pregnancy (BC-P) or the first year post-partum (BC-PP) is rare and whether it differs from breast cancer (BC) in young women not associated with pregnancy is uncertain. We queried our institutional database for BC-P and BC-PP cases and matched controls with BC not associated with pregnancy diagnosed between January 1, 1985 and December 31, 2013. We performed two parallel retrospective cohort studies evaluating clinico-pathologic features, treatment and outcomes for BC-P and BC-PP cases compared to their controls. In our population of 65 BC-P cases, 135 controls for BC-P cases, 75 BC-PP cases and 145 controls for BC-PP cases, high grade and estrogen receptor-negativity were more frequent in both case groups than their controls. Among those with stage I-III BC, patterns of local therapy were similar for both case groups and their controls, with the majority undergoing surgery and radiation. Over three-fourths of those with stage I-III BC received chemotherapy. BC-P cases tolerated chemotherapy well, with the majority receiving doxorubicin/cyclophosphamide every 3weeks. On multivariate analyses of those with stage I-III BC, BC-P cases had non-significantly higher hazards of recurrence and death compared to their controls, while BC-PP cases had non-significantly lower hazards of recurrence and death compared to their controls. BC-P and BC-PP were associated with adverse clinic-pathologic features in our population. However, we did not observe inferior outcomes for BC-P or BC-PP compared to controls, likely due to receipt of aggressive multi-modality therapy.

The association of 18F-fluorodeoxyglucose PET/computed tomography parameters with tissue gastrin-releasing peptide receptor and integrin αvβ3 receptor levels in patients with breast cancer.

Gastrin-releasing peptide receptor (GRPR) and integrin αvβ3 receptors are significantly associated with primary breast cancer, neovascular endothelial, and metastatic tumor cells. We aimed to evaluate GRPR and integrin αvβ3 receptor staining, F-FDG uptake patterns and possible prognostic factors in breast cancer. Ninety lesions of 87 subjects diagnosed with breast cancer were included in this prospective study. The sections were stained with GRPR and integrin αvβ3. Subjects were divided into four molecular subgroups: luminal A, luminal B, triple negative and HER2. PET/CT imaging was performed on all subjects. The groups were compared in terms of GRPR and integrin αvβ3 staining properties, possible prognostic factors and mean SUVmax values. Increased F-FDG uptake was significantly associated with estrogen receptor and progesterone receptor negativity. Molecular subtypes were significantly associated with mean integrin scores (P = 0.030), while histopathological subtypes were significantly associated with mean GRPR scores (P = 0.029). Increased integrin αvβ3 expression is significantly associated with ER and PR negativity. Additionally, GRPR score was significantly correlated with estrogen receptor and progesterone receptor expression scores and a negative statistically significant correlation was detected between integrin and progesterone receptor scores. Mean primary lesion SUVmax had a statistically significant positive correlation with integrin αvβ3 score. GRPR and integrin αvβ3 expression results are complementary to F-FDG PET/CT findings, and are also significantly correlated with hormone receptors associated with aggressive subtypes. These results may pave the way for GRPR and integrin αvβ3 targeted imaging with Ga-labeled molecules and systemic radionuclide treatment with Lu-labeled compounds.

Investigation of the neoclassical ambipolar electric field in ion-root plasmas on W7-X

The role of the radial electric field in high-performance ion-root plasmas on Wendelstein 7-X (W7-X) is examined and compared with neoclassical predictions. The W7-X stellarator is the world’s first large-scale optimized stellarator. One of the important targets chosen for optimization during the W7-X design process was the reduction of core neoclassical heat transport. This optimization was targeted for reactor-relevant high-density plasmas with in which the neoclassical ambipolar radial electric field is expected to be negative throughout the plasmas core.Measurements of the core radial electric field (Er) have confirmed that ion-root conditions (negative Er in the plasma core) have been achieved in W7-X with high-density plasmas and central ECRH. These measured Er profiles agree well with the neoclassical ambipolar Er predicted by the code sfincs. This good agreement provides confidence in the validity of neoclassical calculations in high-density ion-root conditions, and enables initial studies on the role of neoclassical transport in the optimized high-density regime of W7-X.Profile measurements of electron temperature (Te), ion temperature (Ti) and electron density (ne) along with approximations for the average value of have been used as inputs to the sfincs code to calculate the ambipolar Er profile along with neoclassical ion and electron energy flux profiles (, ). Finally the total experimental energy input to the plasma from ECRH heating has been compared to the neoclassical energy fluxes to provide a first estimate for the fraction of transport that can be attributed to neoclassical processes in reactor-relevant high-density ion-root conditions.

Abstract P5-02-09: The prevalence of invasive lobular carcinomas with unconventional immunohistochemical phenotypes

Abstract Background The prognosis of invasive lobular carcinoma (ILC) is controversial. Some studies report equivalent or better outcomes than invasive ductal carcinoma, likely due to ILC’s favorable prognostic phenotype. Classic ILC (CL) is typically of low histologic grade, estrogen receptor (ER) positive and human epidermal growth factor receptor-2 (HER2) negative. However, worse long term outcomes have been observed because ILC tends to be multicentric, bilateral, and to show higher rates of late metastases in uncommon sites. Additionally, subtypes of ILC, including solid (SOL) and pleomorphic (PL), have been reported to display more aggressive behavior. Yet current treatment paradigms are distinguished by hormone receptor profile and stage, not by tumor morphology. This study aimed to evaluate the clinicopathologic and immunohistochemical (IHC) characteristics of ILC, particularly those with unusual patterns. Methods From 2009-2018, consecutive in-house biopsy and resection specimens with the diagnosis of ILC were identified by a retrospective review of our institutional database. Demographic, morphologic, and IHC data were obtained from pathology reports. Cases with equivocal HER2 IHC results are sent for fluorescence in situ hybridization analysis at our Center. CL ILC was defined by small cells with low nuclear grade and discohesive growth arranged in single file or cords. PL ILC is composed of larger, more atypical cells, which still exhibit discohesion typical of lobular phenotype. SOL ILC consists of tumors growing in large sheets with minimal intervening stroma. Results Over the nine year study period, a total of 3,028 ILCs from 2,322 patients were identified. Most (74%, 2229/3028) cases were classified as CL while 22% (665/3028) were PL and 4% (134/3028) SOL (Table 1). The median patient age was 60 years (range 32-95). The median tumor size was larger for PL (2.3 cm) and SOL (2.4 cm) subtypes than CL (1.1 cm). IHC results were available for 896 specimens. The majority of all ILCs showed an expected phenotype: ER positive and HER2 negative (99% CL, 84% PL, 97% SOL). A smaller subset of ER positive ILC were also HER2 positive (1% CL, 8% PL, 3% SOL). No CL or SOL ILC were ER negative; in contrast 8% (21/270) of PL ILC were ER negative. Twelve (5%) PL ER negative cases were also HER2 negative. Overall, 15% of ILC were HER2 positive, with the PL variant showing the highest incidence (11%, 30/270). Lymph node (LN) metastases were seen in 22% (66/291) of CL cases, 55% (53/96) PL and 29% (17/58) SOL. Metastases in 10 or more LN (N3) was seen only in PL and SOL cases (13% and 5%, respectively). Conclusions In this study, up to 8% of ILC cases were found to be ER negative, a finding unique to the PL variant. No CL or SOL ILC was ER negative. HER2 positivity, not typically expected in ILC, was seen in 15% of cases, most commonly in the PL type. ILC that was both negative for ER and HER2 was observed in 5% of cases, and only within the PL subgroup. PL ILC showed higher median tumor size at presentation than CL and nodal metastases were also more common in PL than in CL or SOL ILC (55% vs 22% and 29%, respectively). Our findings are in keeping with prior observations that compared to CL ILC. PL ILC exhibits features associated with unfavorable clinicopathologic features, such as higher tumor and nodal stage at presentation. Additionally, this is the first study to systematically examine the prevalence of unconventional IHC phenotypes of ILC (ER negativity and/or HER2 positivity) in a large series from one institution. Table 1. Summary of Clinicopathologic FeaturesClassicPleomorphicSolidILC types (n=3028)2229665134Median age, (range)60 yrs (32-94)61 yrs (31-95)66 yrs (44-93)Median size, cm 1.12.32.4Immunophenotype (n=896)ER+/HER2-99% (551/559)84% (228/270)97% (65/67)ER+/HER2+1% (8/559)8% (21/270)3% (2/67)ER-/HER2+0% (0/559)3% (9/270)0% (0/67)ER-/HER2-0% (0/559)5% (12/270)0% (0/67)Lymph node status (n=445)N077% (225/291)45% (43/96)71% (41/58)N120% (59/291)31% (30/96)19% (11/58)N22% (7/291)11% (11/96)5% (3/58)N30% (0/291)13% (12/96)5% (3/58) Citation Format: Matthew G Hanna, Anne Grabenstetter, Dara S Ross, Lee K Tan. The prevalence of invasive lobular carcinomas with unconventional immunohistochemical phenotypes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-09.

Abstract P3-08-08: Prognostic and predictive impact of stroma cells defined by platelet derived growth factor receptor beta in early breast cancer: Results from the randomized SweBGR91RT trial

Abstract Background: Although preclinical studies have indicated that stroma cells can modulate the radiosensitivity of tumor cells, non-leukocytic stroma cells have not yet been explored as potential predictive markers for radiotherapy (RT) through systematic analyses of clinical samples. Platelet-derived growth factor receptor beta (PDGFRb) is a key regulator of fibroblasts, pericytes and smooth muscle cells. A high expression of PDGFRb in tumor-associated stroma has previously been associated with worse recurrence free and breast cancer specific survival as well as reduced tamoxifen sensitivity in invasive breast cancer. Purpose: To analyze the prognostic and predictive impact of stromal PDGFRb regarding ipsilateral breast tumor recurrence (IBTR) and any recurrence in a large randomized RT trial. Methods: Stromal PDGFRb expression was assessed by immunohistochemical staining of tissue microarrays (TMAs) with 958 tumors from the SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy). The trial enrolled node-negative, stage I or IIA breast cancer patients, who were randomized to postoperative RT or not after breast conserving surgery. Stained TMAs were evaluated by two independent raters for PDGFRb staining intensity (0/negative; 1/low; 2/moderate; 3/high) and positive stroma fraction (0/0%; 1/1-10%; 2/11-50; 3/51-75%; 4/76-100%). The evaluations of both raters were averaged and the product between the two scoring metrics was formed. For final analysis the data was split in tertiles, as predefined, and referred to as PDGFRb low, medium or high score group. Outcomes were analyzed at 10 years of follow-up. Results: A high PDGFRb score was correlated with ER negativity (p=0.003,), young age (p&amp;lt;0.001), large tumor size (p=0.058) and high histological grade (p=0.067) in Spearman’s Rank test. With regard to prognosis, a significantly increased risk for any recurrence was detected in univariable analysis for patients with a medium (HR 1.57, CI95% 1.11-2.23, p=0.011) or high PDGFRb score (HR 1.49, CI95% 1.06-2.10, p=0.021) compared to the PDGFRb low score group. The significance remained for the PDGFRb medium (HR 1.47, CI95% 1.03-2.11, p=0.034) but not the PDGFRb high score group (HR 1.32, CI95% 0.93-1.88, p=0.125) in a multivariable analysis including grade, age and RT. The benefit of RT regarding the risk of IBTR was significant in the PDGFRb low (HR 0.28, CI95% 0.12-0.65, p=0.003) and medium (HR 0.32, CI95% 0.16-0.61, p=0.001) score groups but not in the PDGFRb high (HR 0.61, CI95% 0.35-1.07, p=0.086) score group in a multivariable analysis including grade and age. The risk reduction from RT regarding any recurrence was also less pronounced in the PDGFRb high (HR 0.73, CI95% 0.48-1.12, p=0.149) score group compared to the PDGFRb low (HR 0.57, CI95 0.32-1.03, p=0.065) and medium (HR 0.46, CI95% 0.28-0.75, p=0.002) score groups in multivariable analysis. No significant interaction between RT and PDGFRb expression could however be detected for IBTR (p=0.14) or any recurrence (p=0.33). Conclusion: A higher PDGFRb score conferred a negative prognosis with increased risk of any recurrence in univariable analyses, which in part can be explained by its association with ER negativity, young age and grade. A predictive effect of RT benefit from PDGFRb could not be confirmed although a tendency toward less benefit was observed in the patient group with the highest PDGFRb score. Citation Format: Carina Strell, Reidunn J Edelmann, Axel Stenmark Tullberg, Per Malmström, Mårten Fernö, Arne Östman, Erik Holmberg, Per Karlsson. Prognostic and predictive impact of stroma cells defined by platelet derived growth factor receptor beta in early breast cancer: Results from the randomized SweBGR91RT trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-08.