Nonmetastatic Breast Carcinoma Research Articles

Immunohistochemistry analysis of autophagy-related proteins Beclin-1, p62/SQSTM1, and LC3B in breast carcinoma progression to bone metastasis

Autophagy is a catabolic pathway involved both in tissue homeostasis and in cellular response to stress. The precise role of autophagy in cancer is still undefined and seems to depend on the tumor stage, appearing tumor-suppressive in physiological conditions and helpful to tumor progression in the established tumor. Here we analyzed by immunohistochemistry Beclin-1, p62, and LC3B, autophagic markers, in human specimens of normal breast, bone metastasis together with pair-matched invasive breast carcinoma of no special type (IBC-NST) as well as non-metastatic breast carcinoma, to disclose the possibility that they could be early prognostic indicators of the evolution of the disease toward the worst outcome. Different regions of metastatic carcinomas, i.e., areas adjacent to the tumor without signs of neoplastic growth, dysplastic lesions, and areas with invasive growth were considered. The pattern of autophagic parameters showed differences among the stages of breast carcinoma progression with a trend that indicated the activation of autophagic process in normal breast (Beclin-1 more elevated than p62), a pattern that was maintained in non-metastatic carcinoma. As the neoplasia proceeds with malignancy, the modification of the pattern of expression of autophagic markers (low ratio between Beclin-1 and p62) in areas of invasive growth of carcinomas suggested inhibition of the process. Of note, the parameters showed a different pattern in bone metastasis with respect to bone metastatic (bm)-IBC-NST, suggesting the reactivation of the autophagic process in the new growth site, helpful to the colonization. The course of autophagy markers during tumor progression could have a prognostic value towards bone metastasis and reveal different roles of the process in different phases of neoplastic growth. The understanding of the role of autophagy in bone metastasis could disclose new therapeutic targets to improve the conditions of patients.

Abstract A072: Ghrelin deletion reduces mammary tumor growth and enhances response to immunotherapy

Abstract Ghrelin is a peptide hormone, primarily produced in the stomach, best known for its role as a regulator of nutrient sensing, appetite, and meal initiation. However, increasing evidence supports a more complex and nuanced role for ghrelin in a diverse array of biological processes, including cancer. Ghrelin’s effects on breast cancer development and progression are not clear, as the literature detailing its effects is conflicting. Several studies in breast cancer survivors have concluded that higher expression of ghrelin is correlated with better recurrence-free and breast cancer-specific survival. However, additional clinical and foundational science studies have suggested greater complexity for ghrelin’s role in breast cancer development as a splice variant of ghrelin, namely In1-ghrelin, is associated with increased tumor proliferation and reduced disease-free survival of breast cancer patients. Thus, the current study sought to determine the effects of ghrelin deletion within mammary tumor cells (67NR) on subsequent tumor growth. Specifically, we hypothesized that ghrelin deletion would significantly alter tumor growth. Adult female mice received bilateral orthotopic injections of the nonmetastatic murine breast carcinoma cell line 67NR or one of two CRISPR generated ghrelin deleted cell lines 1G9 or 2G2 (derived from the 67NR cell line). Ghrelin deletion significantly reduced tumor volume and tumor mass by ~60% and ~55%, respectively. Additionally, ghrelin deletion significantly increased median survival duration by ~30%. When examining changes within the tumor microenvironment we observed a significant increase in macrophage colonization in ghrelin knockouts relative to the parental 67NR tumors. Notably, the percent F4/80 staining within the tumor positively correlated with length of survival. To determine the role of these F4/80 cells on tumor progression, we ablated these macrophages by feeding chow containing the colony stimulating factor receptor 1 inhibitor, PLX5622, for the entirety of the study. Ablating macrophages significantly increased tumor volume and tumor mass and rendered the previous beneficial effects of ghrelin deletion null, suggesting that the positive effects of ghrelin deletion may be due to actions on macrophages. Lastly, because of the increased macrophage infiltration within ghrelin knockout tumors, we sought to determine their repose to an immunotherapy targeting macrophages, namely anti-CD47. Notably, ghrelin deleted tumors displayed a positive response to the immunotherapy and further reduction in tumor growth (~80% reduction in tumor volume compared to 67NR tumors). Whereas, 67NR tumors were unresponsive to the immunotherapy. These data add to the literature detailing the complex effects of ghrelin on tumor growth and suggest that ghrelin may be a druggable target to slow tumor development. Citation Format: William H Walker II, Brittany D Elliott, Claire O Kisamore, Randy J Nelson, A. Courtney DeVries. Ghrelin deletion reduces mammary tumor growth and enhances response to immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A072.

Breast Carcinoma With Tubulopapillary Features Has a Distinct Immunophenotypic and Molecular Signature: A Report of Two Tumors and Literature Review.

Breast carcinoma with tubulopapillary features is a newly described entity associated with poor prognosis with only 14 tumors reported in the literature. We report 2 additional tumors and identify novel immunohistochemical and molecular features of the tumor. The first tumor was from a 72-year-old woman with nonmetastatic breast carcinoma and the second was from a 32-year-old woman with metastatic breast carcinoma who received neoadjuvant therapy. Both tumors had high-grade nuclear features with a distinctive morphology characterized by infiltrating open glands with intratubular papillary and micropapillary projections in >90% of the invasive carcinoma. In addition to the usual predictors of aggressive behavior, both tumors showed a high expression of p16 and SOX10, which has not been previously described. Targeted tumor sequencing revealed pathogenic variants of TP53 in both tumors, in agreement with previous reports. Prior studies have shown a correlation between p16 and SOX10 expression with high-grade features and worse prognosis; typically seen in triple-negative carcinomas as demonstrated in both of our tumors. However, not all reported tumors of breast carcinoma with tubulopapillary features have demonstrated a triple-negative profile as there are a few reports of tumors with estrogen receptor and/or human epidermal growth factor 2 expression. Due to their distinct morphologic and molecular characteristics, breast carcinoma with tubulopapillary features may represent a new breast cancer histologic subtype.

Évaluation prospective des dysthyroïdies radio-induites après irradiation mammaire et sus-claviculaire

PurposeThe thyroid is an endocrine gland playing a major role in metabolism and development by the secretion of T4 and T3 thyroid hormones. Due to its anatomical position, it is often included in the target volume for the irradiation of certain tumours and thus receives significant doses (10 to 80Gy). The treatment of breast cancer requires in most cases a breast irradiation associated or not with a lymph node irradiation. The aim of our study was to investigate prospectively the frequency of thyroid disorders in patients with breast cancer treated by radiation, with or without irradiation of the supra- and subclavicular lymph nodes. Material and methodsThis prospective multicentre study (institut Godinot, institut de cancérologie Strasbourg Europe and institut de cancérologie de Lorraine) concerned adult patients with non-metastatic breast carcinoma treated by adjuvant irradiation. They were included in a non-randomized way between February 2013 and June 2015 and divided into two groups according to treatment: (i) breast radiotherapy associated with irradiation of the supra- and subclavicular lymph nodes (group 1), or (ii) breast irradiation alone (group 2). The dose – volume histogram of the thyroid was systematically edited by the physics department. Each patient had a consultation with an endocrinologist at the beginning of the treatment and was monitored by blood analyses including TSH, T4L, antithyroglobulin and antiperoxidase antibodies every 6 months until the 60th month after the end of radiotherapy. Data were described by numbers and percentages for qualitative variables; by means, medians, standard deviation and ranges for quantitative variables. Statistical associations were tested by Chi2, Fisher's, Student's, or analysis of variance tests depending on the conditions of application. Survival analyses were performed by log rank tests and Cox models. ResultsThis study initially included 500 patients, 245 in group 1 and 252 in group 2 (three patients were later excluded for false inclusion). Thyroid abnormalities occurred in 76 patients, representing an incidence of 15.3%. The mean time of the first occurrence of thyroid disorders was 24.3 months. It was more frequent in group 1 with a prevalence of 19.2% against 11.5% in group 2 (P=0.01745). A maximal radiation dose delivered to the thyroid gland greater than 20Gy (odds ratio [OR]: 1.82; P=0.018) or 30Gy (OR: 1.89; P=0.013) was significantly associated with a higher incidence of thyroid disorders, as was a mean dose greater than 30Gy (OR: 5.69; P=0.049). A percentage of thyroid volume receiving 30Gy (V30) greater than 50% (P=0.006) or greater than 62.5% (P=0.021) was significantly associated with an increased incidence of thyroid disorder and more precisely, hypothyroidism (P=0.0007). In multivariate analysis, no factor associated with the occurrence of thyroid disorder was identified. However, in the subgroup analysis concerning group 1 (receiving supraclavicular irradiation), a maximal radiation dose greater than 30Gy appeared to be a risk factor for the occurrence of thyroid disorders (P=0.040). ConclusionThyroid disorder, and in particular hypothyroidism, may be a late side effect of locoregional breast radiotherapy. Patients receiving this treatment should have a biological monitoring of thyroid function.

Long-term efficacy and tolerance of a technique for postmastectomy electron beam radiation therapy of the unreconstructed chest wall and lymph node areas for non-metastatic breast cancers

PurposeTo evaluate the long-term tolerance and outcome of patients irradiated with an electron beam technique used since 2007 on the chest wall and lymph node areas after mastectomy for non-metastatic locally advanced breast carcinoma. Patients and methodsAll patients irradiated with an improved electron beam technique after mastectomy for non-metastatic breast carcinoma between 2007 and 2011 at Institut Curie (France) were included in this descriptive study. The technique has already been described in other studies, as has its 5-year tolerance and non-inferiority compared to photon irradiation. Acute and chronic toxicity were collected using CTCAE v 3.0. A clinical examination was carried out each week during the radiotherapy and at each 6 months consultation with one mammogram per year at the Institut Curie for at least 5 years. The patients then continued to be followed either at the Institut Curie or in private practice with a good transmission of outpatient consultations, thanks to a system of forms to be completed and integrated into the electronic files. Quantitative and qualitative data are defined by mean and proportion. Statistical comparisons were made by computer using the Chi2 test and Fisher's exact test for categorical variables. Recurrence-free survival was defined as the time between the end of treatment and the date of recurrence or death. Overall survival was defined in the same way without taking into account recurrences. Patients who did not report any events were censored at the date of last news. ResultsOf the 796 patients included, 51.3% had multifocal lesions, 10.1% had triple negative status, and 18.8% displayed overexpression of the Her2 receptor, 196 (24.6%) patients received neoadjuvant chemotherapy and 208 (26.1%) systemic treatment during radiotherapy (chemotherapy or targeted therapy); 514 (64.6%) had at least one positive lymph node. The internal mammary chain (IMC) was irradiated in 85.6% of cases, the supraclavicular areas in 88.3% of cases, the infraclavicular in 77.9% of cases and the axillary area in 14.9% of cases. With a median follow-up of 113 months (range: 2–164 months), locoregional recurrence-free survival and overall 10-year survival was respectively 94.02%, (95% CI: 92.13–98.94) and 79.84% (95% CI: 76.83–82.97). Median survival was not reached. In the long term, 29.6% of patients had telangiectasias (grade 1: 23.3%, grade 2: 5.2%, grade 3: 1.1%). There were 279 patients (35.1%) with secondary breast reconstruction on average 21 months after all treatments. IMC irradiation was not associated with a majority of pulmonary toxicity. Thirty-five patients developed chronic heart disease after radiotherapy, 30 of whom had received anthracyclines and 9 had received traztuzumab. Three of these reported a coronary ischaemic event, including 2 irradiated on the left and 1 on the right, the 4 were irradiated in the vicinity of the IMC and the other lymph node areas, but presented many other cardiovascular risk factors (between 2 and 4). During follow-up, 4.9% of patients had a contralateral recurrence (n=39) and 5.5% had a second non-breast cancer (n=44), of the 6 bronchopulmonary cancers diagnosed, none appeared to be related to chest wall radiotherapy. ConclusionThis study confirms that the improved postmastectomy electron beam radiation therapy technique is well-tolerated after nearly 10 years of follow-up.

A hierarchical approach to combine histological grade and immunohistochemical factors to identify high-risk luminal breast cancers.

BackgroundThe luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions.MethodsA retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I–III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan–Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors.ResultsDuring a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316–0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286–0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415–1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403–1.088), p = 0.104).ConclusionThe semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.

Prognostic value of programmed death ligand-1 expression in breast carcinomas

ObjectivesTo assess the prognostic value of programmed death ligand-1 (PDL-1) expression in patients with nonmetastatic breast carcinoma patients both in tumor cells and tumor-infiltrating lymphocytes (TILs).BackgroundPDL-1 has emerged as important immune biomarkers in breast cancer. It can be targeted with immunotherapy, which represents a significant advancement in the management of this disease.Patients and methodsParaffin blocks of patients with breast cancer will be tested for the expression of PDL-1 both on TILs and malignant epithelial cells and correlated with patients and disease features.ResultsThis retrospective study included 60 patients. PDL-1 expression was positive in 33 (55%) patients on TILs and was positive in tumor cells in 27 (45%) patients of the studied patients. There was no significant relation between PDL-1 expression on TILs and patients and disease features. There was significant relation between positive PDL-1 expression on epithelial cells and triple-negative breast cancer, estrogen receptor negative, progesterone receptor negative status (P = 0.006, 0.006, and 0.006). PDL-1 intensity in intratumoral lymphocytes is significantly related to tumor stage (P = 0.006). PDL-1 H score in malignant epithelial cells was significantly related to disease stage (P = 0.021). Tumor size, HER-2neu status, and PDL-1 H score on malignant epithelial cells were independent risk factors for disease progression.ConclusionPDL-1 expression is common in both malignant tumor cells and TILs. A higher PDL-1 H score on malignant epithelial cells was associated with longer time to progression.

Higher platelet counts correlate to tumour progression and can be induced by intratumoural stroma in non-metastatic breast carcinomas.

Platelets support tumour progression. However, their prognostic significance and relation to circulating tumour cells (CTCs) in operable breast cancer (BrCa) are still scarcely known and, thus, merit further investigation. Preoperative platelet counts (PCs) were compared with clinical data, CTCs, 65 serum cytokines and 770 immune-related transcripts obtained using the NanoString technology. High normal PC (hPC; defined by the 75th centile cut-off) correlated with an increased number of lymph node metastases and mesenchymal CTCs in the 70 operable BrCa patients. Patients with hPC and CTC presence revealed the shortest overall survival compared to those with no CTC/any PC or even CTC/normal PC. Adverse prognostic impact of hPC was observed only in the luminal subtype, when 247 BrCa patients were analysed. hPC correlated with high content of intratumoural stroma, specifically its phenotype related to CD8+ T and resting mast cells, and an increased concentration of cytokines related to platelet activation or even production in bone marrow (i.e. APRIL, ENA78/CXCL5, HGF, IL16, IL17a, MDC/CCL22, MCP3, MMP1 and SCF). Preoperative platelets evaluated alone and in combination with CTCs have prognostic potential in non-metastatic BrCa and define patients at the highest risk of disease progression, putatively benefiting from anti-platelet therapy.

A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved\xa0survival in non-metastatic triple-negative breast carcinoma

BackgroundTriple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC.MethodsRetrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry.ResultsWe observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS.ConclusionTNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.

Research on the Role of Combined Chemotherapy and Radiotherapy in Patients With N+ Non-Metastatic Metaplastic Breast Carcinoma: A Competing Risk Analysis Model Based on the SEER database, 2000 to 2015.

PurposeDue to the rarity of metaplastic breast carcinoma (MpBC), no randomized trials have investigated the role of combined chemotherapy and radiotherapy (CCRP) in this condition. We aimed to explore and identify the effectiveness of CCRP in patients with regional lymph node metastasis (N+) non-metastatic MpBC.Materials and MethodsData were obtained from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program database. We assessed the effects of CCRP on overall survival (OS), breast cancer-specific survival (BCSS), and breast cancer-specific death (BCSD) using Kaplan-Meier analysis, competing risk model analysis, and competing risk regression mode analysis.ResultsA total of 707 women and 361 death cases were included in the unmatched cohort, of which 76.45% (276/361) were BCSD, and 23.55% (85/361) were non-breast cancer-specific deaths (non-BCSD). Both the ChemT and CCRP groups had better OS (ChemT group: HR: 0.59, 95% CI: 0.45–0.78, P<0.001; CCRP group: HR: 0.31, 95% CI: 0.23–0.41, P<0.001) and BCSS (ChemT group: HR: 0.63, 95% CI: 0.45–0.87, P<0.001; CCRP group: HR: 0.32, 95%CI: 0.22–0.46, P<0.001) than the non-therapy group. Subjects in the CCRP group tended to have significantly lower cumulative BCSD (Gray’s test, P=0.001) and non-BCSD (Gray’s test, P<0.001) than the non-therapy group or ChemT group. In competing risk regression model analysis, subjects in the CCRP group had a better prognosis in BCSD (HR: 0.710, 95% CI: 0.508–0.993, P=0.045) rather than the ChemT group (HR: 1.081, 95% CI: 0.761–1.535, P=0.660) than the non-therapy group.ConclusionOur study demonstrated that CCRP could significantly decrease the risk of death for both BCSD and non-BCSD and provided a valid therapeutic strategy for patients with N+ non-metastatic MpBC.

Analysis of Serum Vitamin D and Major Histocompatibility Complex Class I-Related Chain a (Mica) Levels in Patients With Breast Carcinoma

Introduction: Breast carcinoma is the most deadly cancer in women worldwide, with an incidence rateof 26 cases per 100,000 women in Indonesia. Treatment and prognosis is very dependent on the stage ofbreast carcinoma. Vitamin D can inhibit proliferation and invasive cancer cells, induction of differentiation,apoptosis and promotion of angiogenesis. Major Histocompatibility Complex class I - related chain A(MICA) plays a role in reducing the expression of NKG2D receptors in breast carcinomas so that they canbe targeted for treatment of breast carcinoma treatment. The aim of this study was to determine vitamin Dand MICA levels in serum patients with non-metastatic and metastatic breast carcinoma.Method: We examined 86 samples of breast carcinoma patients (44 non-metastatic samples and 42metastatic samples) with a range of 29 - 68 years old. Vitamin D levels were examined by the EnzymeLinked Flourescent Assay (ELFA) method while the MICA levels were examined by Enzyme LinkedImmunoabsorbant Assay (ELISA).Result: There were significant differences in mean vitamin D levels in non-metastatic and metastatic breastcarcinomas (29.88 ng/mlvs19.06 ng/ml; p &lt;0.01).Serum MICA levels in patients with non-metastatic breastcarcinoma were lower (333.52 pg/ml) than in metastatic breast carcinoma(333.52 pg/mlvs528.71 pg/ml; p&lt;0.01).A negative correlation was found between vitamin D levels andMICA in both groups (Pearson correlation, p: -0.58).Conclusion: Metastatic breast carcinoma had lower vitamin D levels and higher serum MICA levels thannon-metastatic breast carcinoma.

Appropriate management and long-term outcomes of older women with breast carcinoma in Umbria (Italy)

Abstract Background Age is an important risk factor for breast cancer, which represents the most common malignancy and the leading cause of cancer death among women aged ≥50 years. International recommendations suggest that fit older women could gain similar benefit from adjuvant treatments as younger patients. The aim of our study is to estimate the average predicted probability (APP) of receiving non-adherent-to-guidelines adjuvant treatments, 5-years relative survival (5y-RS) and relative excess risk of death (RER) in older women with primitive invasive non-metastatic breast carcinoma in Umbria in 2001-2014. Methods We analyzed high-quality data from the Umbrian Cancer Registry. Women aged 50-89 years were grouped according to eligibility criteria for each adjuvant treatment: hormone therapy, radiotherapy, and chemotherapy. We estimated the APP and, for women aged 50-79 years, the 5y-RS (Pohar-Perme method) and RER. Results Age affected the APP of receiving non-adherent-to-guidelines treatments. In the age group 70-79, the 5y-RS was higher in women receiving adherent-to-guidelines treatments: hormone therapy (96.81, 95% CI 93.46-98.46 vs 77.70, 95% CI 67.64-84.97), radiotherapy (96.60, 95% CI 92.75-98.42 vs 77.46, 95% CI 69.73-83.44) and chemotherapy (83.81, 95% CI 75.99-89.27 vs 70.26, 95% CI 60.15-78.26). The RER was significantly higher in women receiving non-adherent-to-guidelines hormone therapy in any age group and radiotherapy in women aged 60-69 (4.55, p &amp;lt; 0.001) and 70-79 years (6.14, p &amp;lt; 0.001). Conclusions The oldest age group showed the highest APP of non-adherence-to-guidelines. Non-adherence-to-guidelines was associated with worse long-term outcomes at any age. Our findings suggest a further awareness on the importance of therapeutic strategy adhering to evidence-based recommendations. Key messages Older women with invasive breast carcinoma tend to receive non-adherent-to-guidelines treatments. Non-adherent-to-guidelines therapeutic strategy correlates with worse health outcomes.

The prognostic value of lymph node ratio in survival of non-metastatic breast carcinoma patients.

This study was conducted to assess the correlation between lymph node ratio (LNR) and prognosis of non-metastatic invasive breast carcinoma. This retrospective study examined 455 patients who were diagnosed with non-metastatic, unilateral invasive breast carcinoma and underwent either breast conservative surgery (BCS) or modified radical mastectomy (MRM) with axillary lymph node dissection (ALND) with at least one lymph node identified in the ALND specimen. Receiver operating characteristics (ROC) curve analysis was used to find out predictive cut-off values of the LNR and negative lymph nodes (NLN). The median follow-up duration was 38months. The median DFS and OS were 68months and 72months, respectively. 25.1% of patients had reported recurrence. The optimal cut-off value of LNR was 0.40. LNR was found to correlate significantly with pathological T (p < 0.001), pathological N (p < 0.001), and NLN (p < 0.001). Univariate analysis of the patients showed that the age group ≤ 35years, menstrual status, pathological T, nodal status, lymphovascular invasion (LVI), perineural invasion (PNI), tumor grade, estrogen receptor (ER), progesterone receptor (PR), molecular subtypes, LNR, and NLN can affect disease-free survival (DFS) (p < 0.05) and OS (p < 0.05). Multivariate analysis showed that the pathological T (p < 0.001), menstrual status (p = 0.030), and LNR (p < 0.001) were the independent prognostic factors for DFS. Pathological T (p < 0.001) and LNR (p < 0.001) were the independent prognostic factors affecting OS. LNR is the independent prognostic factor of DFS and OS for non-metastatic breast carcinoma.

Hormone-Independent Mouse Mammary Adenocarcinomas with Different Metastatic Potential Exhibit Different Metabolic Signatures

The metabolic characteristics of metastatic and non-metastatic breast carcinomas remain poorly studied. In this work, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was used to compare two medroxyprogesterone acetate (MPA)-induced mammary carcinomas lines with different metastatic abilities. Different metabolic signatures distinguished the non-metastatic (59-2-HI) and the metastatic (C7-2-HI) lines, with glucose, amino acid metabolism, nucleotide metabolism and lipid metabolism as the major affected pathways. Non-metastatic tumours appeared to be characterised by: (a) reduced glycolysis and tricarboxylic acid cycle (TCA) activities, possibly resulting in slower NADH biosynthesis and reduced mitochondrial transport chain activity and ATP synthesis; (b) glutamate accumulation possibly related to reduced glutathione activity and reduced mTORC1 activity; and (c) a clear shift to lower phosphoscholine/glycerophosphocholine ratios and sphingomyelin levels. Within each tumour line, metabolic profiles also differed significantly between tumours (i.e., mice). Metastatic tumours exhibited marked inter-tumour changes in polar compounds, some suggesting different glycolytic capacities. Such tumours also showed larger intra-tumour variations in metabolites involved in nucleotide and cholesterol/fatty acid metabolism, in tandem with less changes in TCA and phospholipid metabolism, compared to non-metastatic tumours. This study shows the valuable contribution of untargeted NMR metabolomics to characterise tumour metabolism, thus opening enticing opportunities to find metabolic markers related to metastatic ability in endocrine breast cancer.

"First Do No Harm": Significance of Delays from Diagnosis to Surgery in Patients with Non-metastatic Breast Cancer.

The majority of patients with non-metastatic breast cancer will undergo surgery. This involves complex decisions that inevitably increase time from diagnosis to surgery beyond the currently recommended 30days. This study aims to analyse factors that increase time to surgery and establish whether it is justifiable in the context of improved individualised breast cancer management. A retrospective analysis of all patients at Austin Health surgically managed for non-metastatic invasive breast carcinoma between 2013 and 2019 was conducted. Time to surgery (TTS) was defined as time between informed diagnosis and cancer surgery. The patients were grouped into TTS groups of ≤30days and >30days. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of time interval between diagnosis and surgery. Seven hundred and thirty-one patients were included in our TTS analysis, only half of this cohort received surgery within the recommended 30 days. Many of the factors identified to be associated with increased TTS are the key to optimal management. Median follow-up for the cohort was 30months. Between wait groups of ≤30 and >30days, there were no significant association found between TTS and survival outcomes for DFS (HR 1.20 95% CI 0.56-2.60) and OS (HR 1.58 95% CI 0.82-3.03). Breast cancer management involves complex factors that significantly increase TTS. Surgery within 30days of diagnosis is not associated with improved DFS and OS. Outcomes from this study support a revision of current recommendations for TTS in non-metastatic breast cancer care.

OP1 “First do no harm”: Significance of delays to surgery in patients with non-metastatic breast cancer

Background The majority of patients in Australia with non-metastatic breast cancer will undergo primary surgery with curative intent. This involves many complex decisions that inevitably increase time from diagnosis to surgery. Current guidelines suggest surgery should occur within 30 days of a decision to treat1. However, there may be appropriate reasons to justify a delay to surgery. This study aims to analyse factors that contribute to an increased time to surgery (TTS) and establish whether the associated wait time is justifiable in the context of improved individualised breast cancer management. Methods This is a retrospective analysis of all patients at Austin Health surgically managed for non-metastatic invasive breast carcinoma between 20013 and 2019. TTS was defined as time between informed diagnosis and cancer surgery. Patients were categorised into TTS groups of ≤30 and >30 days. Kaplan-Meier survival analysis was used to evaluate the impact of TTS on survival outcomes. Results A total of 842 patients were included. Median number of days to surgery was 34 days. 43.9% of the total cohort received surgery within the recommended 30 days. Factors identified to be associated with an increased TTS were screening, transfer of care, ER positive tumour, mastectomy, immediate reconstruction and use of pre-operative imaging including MRI and staging scans. Median follow up for the cohort was 30 months. Between wait groups of ≤30 and >30 days, there were no significant association found between TTS and survival outcomes for DFS (HR 1.20 95% CI 0.56 to 2.60) and OS (HR 1.58 95% CI 0.82 to 3.03). Conclusions Breast cancer management involves many complex factors that significantly increases time from diagnosis to surgery. Surgery within 30 days of diagnosis is not associated with improved DFS and OS. Time delays associated with integral element of care should be used to guide a revision of current TTS recommendations. 1. Royal Australasian College of Surgeons. Elective Surgery Urgency Categories. 2019.

Correlation between the presence of androgenic receptors and molecular and histopathological variables in breast cancer

Introduction: The expression of androgenic receptors (AR) is a new predictive marker of response and prognosis in invasive breast carcinoma (BC). It emerges as a potential therapeutic target. Objective: To evaluate the frequency of AR positivity and its correlation with molecular and histopathological parameters in infiltrative BC. Method: Retrospective cohort study, analyzing 119 cases of invasive non-metastatic BC, seen at a private clinic. Hormonal receptors were screened by immunohistochemical reaction, and AR were considered positive when present in at least 10% of cells, ER and PR from 1%. This finding was correlated with pathological staging, histological grade (HG), vascular-lymphatic invasion (VLI), estrogen (ER) and progesterone receptors (RP), HER2 and Ki 67. Results: Androgen receptors were positive in 80.6% of cases. In the assessment of pathological staging, of the 63 patients with stage I, 81% showed positive androgen receptors, while among the 28 patients with stage II, 75% had positive androgen receptors, and 88% of the 17 patients with stage III presented the positivity of the recipient. Regarding the histological parameters of the tumor, 16 patients had grade 1 tumors, 93.7% of them with positive androgen receptors, while among the 63 with grade 2 tumors 90.4% had androgen receptor positivity, and only 59, 3% of the 27 tumors evaluated as grade 3 had a positive androgen receptor. The vascular-lymphatic invasion was negative in 57 patients, 78.9% of the tumors with positive androgen receptor. Among the 56 tumors with positive vascular-lymphatic invasion, 85.7% had an androgen receptor positivity. In the immunohistochemical evaluation of tumors, among the 95 patients with positive estrogen receptors, 91.5% also had positive androgen receptor, which was positive in only 37.5% of the 24 patients with negative estrogen receptors. Of the 21 patients who had tumors with overexpressed HER, 85.7% also had positive androgen receptors, which were also positive in 86.4% of 96 without overexpression of HER2. In the evaluation of cell proliferation by the Ki67 antigen, among the 50 tumors with Ki67 &lt;20%, 94% had positive androgen receptors, while 83.7% were positive among the 49 tumors with Ki67 between 20 and 50% and only 35% positivity of androgen receptors in 17 tumors with Ki67&gt; 50%. Conclusions: AR positivity is associated with more differentiated hormone-dependent tumors with a lower proliferation rate.

18F-fluorodeoxyglucose PET/computed tomography in locoregional staging and assessment of biological and clinical aggressiveness of breast cancer subtypes.

We aimed to evaluate the availability of fluorine-18-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) in initial axillary lymph node (ALN) staging in breast cancer. The secondary objective is to evaluate the role of FDG PET/CT as a pretest in sentinel lymph node biopsy vs. axillary lymph node dissection when predicting disease aggressiveness. The study evaluated retrospectively 194 breast cancer patients who underwent preoperative 18F-FDG. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FDG PET/CT for ALN metastases were confirmed with histopathology as the gold standard. The value of the area under curve (AUC), sensitivity and specificity for ALN metastases were determined as 0.847, 78.8% and 92.6%, respectively. The cut-off value of the maximum standardized uptake value (SUVmax) for metastatic ALN detection was calculated as 1.79. PPV, NPV and the accuracy of 18F-FDG PET/CT were 0.933 (93.3%), 0.75 (75%) and 0.837 (83.7%), respectively. The SUVmax value of the primary lesion was significantly correlated with grade, estrogen receptor (ER) status, progesterone receptor (PR) status, SUVmax value of metastatic ALN, Her-2 status and Ki-67 level. Molecular subtypes revealed no statistically significant difference in terms of mean SUVmax value. High values of AUC, sensitivity, specificity, NPV and PPV encourage utilization of PET/CT for locoregional staging of nonmetastatic breast carcinoma. The significant correlation between the primary tumor SUVmax value and grade, ER status, PR status and Ki-67 level increases the prognostic predictive value of the preoperative PET/CT.

Abstract P1-03-03: Comparing staging assignments based on the 7th and 8th editions of the American Joint Committee on Cancer staging system for breast cancer

Abstract Background: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer has redefined breast cancer staging to better represent the heterogeneity of the disease. The previously established TNM system reflected only tumor size (T), nodal status (N), and distant metastasis (M). The updated staging system introduces new clinical and pathological prognostic staging systems by incorporating tumor grade, tumor markers, and genomic assays. Prospective comparisons of staging assignment between AJCC 7th and 8th edition staging systems have not been performed in the United States. The objective of this study was to compare subjects' assigned stage between the AJCC 7th and 8th edition staging systems. Methods: Data were collected from patients with non-metastatic breast carcinoma who presented to the University of Chicago between January 1, 2018 and May 31, 2018. Upstaging or downstaging was defined as an increase or decrease by one or more letter or number stages (i.e. from IIA to IIB or IB). Descriptive data were generated for all collected data. Analysis was performed in Stata 14.0. Results: Clinical anatomic and prognostic stages were assigned to 246 patients while pathologic anatomic and prognostic stages were assigned to 142 patients. Forty-seven patients underwent neoadjuvant therapy and were not assigned a pathologic prognostic stage, while 57 patients had not undergone surgery at our institution by the end of the study period and were not assigned a pathologic stage. Two patients had lobular carcinomia in situ and were no longer considered to have a malignancy by the 8th edition staging system; anatomic staging was otherwise unchanged from 7th edition to 8th edition staging in this cohort. Of the 246 patients assigned clinical anatomic and prognostic stages, 48 patients were upstaged (19.5%), 37 were downstaged (15.0%), and 161 were not affected (65.5%) by prognostic staging. Of the 142 patients assigned pathologic anatomic and prognostic staging, nine patients were upstaged (6.3%), 32 were downstaged (22.5%), and 101 were not affected (71.1%) by prognostic staging. Four patients were eligible to be downstaged in pathologic prognostic staging by genomic assays such as Oncotype (consisting of Stage 1B or higher patients with T1N0M0 HER2 - ER + PR - Grade 3 disease or T2N0M0 HER2 - ER + disease). Of these patients, three had genomic assays performed by the end of the study period. Results from genomic assays did not affect the staging of these three patients. Stage Changes with the AJCC 8th Edition Upstaged % (n)Downstaged % (n)No Change in Stage % (n)Clinical Stage19.5 (48)15.0 (37)65.5 (161)Pathologic Stage6.3 (9)22.5 (32)71.1 (101) Conclusions: Approximately one third of breast cancer patients were assigned new clinical or pathologic stages with the AJCC 8th edition staging system. These findings confirm that implementation of the new criteria for staging will be important to many patients in discussions of treatment and prognosis. Citation Format: Brian R, Tseng J, Bao J, Jaskowiak N. Comparing staging assignments based on the 7th and 8th editions of the American Joint Committee on Cancer staging system for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-03-03.

Cancer: The Tumor-Driven Disease of the Host

Tumors interact reciprocally with their hosts' physiology and metabolism, making cancer a systemic disease. In this issue of Cell Metabolism, Borniger etal. (2018) demonstrate this phenomenon by linking the endocrine control of food intake with sleep behavior and liver metabolism in a mouse model of non-metastatic breast carcinoma.