Intermediate Histological Grade Research Articles

Ultrastructural analysis of prostate cancer tissue provides insights into androgen-dependent adaptations to membrane contact site establishment.

Membrane trafficking and organelle contact sites are important for regulating cell metabolism and survival; processes often deregulated in cancer. Prostate cancer is the second leading cause of cancer-related death in men in the developed world. While early-stage disease is curable by surgery or radiotherapy there is an unmet need to identify prognostic biomarkers, markers to treatment response and new therapeutic targets in intermediate-late stage disease. This study explored the morphology of organelles and membrane contact sites in tumor tissue from normal, low and intermediate histological grade groups. The morphology of organelles in secretory prostate epithelial cells; including Golgi apparatus, ER, lysosomes; was similar in prostate tissue samples across a range of Gleason scores. Mitochondrial morphology was not dramatically altered, but the number of membrane contacts with the ER notably increased with disease progression. A three-fold increase of tight mitochondria-ER membrane contact sites was observed in the intermediate Gleason score group compared to normal tissue. To investigate whether these changes were concurrent with an increased androgen signaling in the tissue, we investigated whether an anti-androgen used in the clinic to treat advanced prostate cancer (enzalutamide) could reverse the phenotype. Patient-derived explant tissues with an intermediate Gleason score were cultured ex vivo in the presence or absence of enzalutamide and the number of ER-mitochondria contacts were quantified for each matched pair of tissues. Enzalutamide treated tissue showed a significant reduction in the number and length of mitochondria-ER contact sites, suggesting a novel androgen-dependent regulation of these membrane contact sites. This study provides evidence for the first time that prostate epithelial cells undergo adaptations in membrane contact sites between mitochondria and the ER during prostate cancer progression. These adaptations are androgen-dependent and provide evidence for a novel hormone-regulated mechanism that support establishment and extension of MAMs. Future studies will determine whether these changes are required to maintain pro-proliferative signaling and metabolic changes that support prostate cancer cell viability.

Abstract 1227: Molecular-based tumor grade predictor for breast cancer, clear cell renal cell carcinoma, and lung adenocarcinoma

Abstract Classifying tumors based on histological grade is used for many cancers to determine a patient’s prognosis and select the appropriate treatment. Although low grade (G1) and high grade (G3/G4) tumors have been shown to predict patient survival in many cancers, an intermediate histological grade (G2) does not have clear prognostic significance. Therefore, to allow a more accurate assessment of a patient’s risk, recent studies have focused on utilizing gene expression data to improve prognostic stratification of tumors into either a high-risk or low-risk group. Here, we present a molecular-based classifier that can use gene expression data from both RNA sequencing (RNA-seq) and microarray profiling to achieve accurate prediction of tumor grade for breast cancer (BRCA), lung adenocarcinoma (LUAD), and clear cell renal cell carcinoma (ccRCC). The tumor grade predictor was developed by training a machine-learning algorithm to classify tumors into categories of low (mG1) and high (mG3/mG4) molecular grades for each cancer type using rank transformation of gene expression data from multiple datasets. This resulted in the revealing of features of the mG3/mG4 groups not shown by histological methods (i.e., the Warburg effect, proliferation signaling pathways, inactivation of tumor suppressors, fibrotic and immunosuppressive microenvironment, and the loss of normal cell morphology), allowing for a more accurate stratification between the high- and low-grade groups. Importantly, by using rank transformation to analyze data from both RNA-seq and microarray profiling, the predictor functioned independent of various sources of batch effect, resulting in the ability to work with single samples and not only datasets. Validation of the tumor grade classifier with pathological classification of G1 and G3/G4 samples from RNA-seq and microarray expression data into mG1 and mG3/mG4 groups showed a more accurate performance than other gene expression-based methods, which was demonstrated by it’s sensitivity-specificity value (AUC scores: BRCA - 0.95, LUAD - 0.89, ccRCC - 0.83). Further, cox-regression analysis showed that prognostic value of mG1 and mG3 groups were comparable to histological grades (BRCA - 0.71 vs. 0.71; LUAD - 0.66 vs. 0.62; ccRCC - 0.74 vs. 0.71), demonstrating the ability of the classifiers to successfully split G2 histological samples into molecular grades. In conclusion, we developed a tumor grade predictor that utilizes expression data from multiple datasets to accurately classify tumors for three cancer types. The resulting prognostic ability of the molecular grades demonstrates their capability of assessing the levels of risk for G2 samples, suggesting the potential for molecular-based tumor grade classifiers to be used in future clinical application. Citation Format: Zoya Antysheva, Maria V. Guryleva, Ivan Valiev, Nikita Kotlov, Viktor Svekolkin, Olga Gancharova, Vladimir Kushnarev, Yuriy Popov, Anna Belozerova, Dmitry Tabakov, Jessica H. Brown, Krystle Nomie, Alexander Bagaev, Nathan Fowler. Molecular-based tumor grade predictor for breast cancer, clear cell renal cell carcinoma, and lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1227.

The relationship of oncotype Dx Recurrence Score (RS) with Ki 67 in early stage breast cancer patients in a community based cancer center in rural central Nebraska.

e12566 Background: Oncotype Dx recurrence score (RS), is a prognostic and predictive test utilized for decision making in adjuvant therapy of 0-3 node/hormone receptor positive(HR+)/ HER-2-negative early breast cancer. Ki-67 is a marker of proliferating cells and is associated with prognosis and response. Immunohistological (IHC) assessment of Ki 67 expression is less expensive and with the approval of CDK inhibitors in the high risk adjuvant setting, it is increasingly being utilized in clinical decision making. A moderate to strong correlation between Ki67 and Oncotype Dx RS has been reported in the literature. We sought to examine the relationship of Ki 67 to Oncotype Dx RS in a community-based cancer center in rural central Nebraska. Methods: Forty-three consecutive postmenopausal breast cancer patients(pts) diagnosed and treated at our community based cancer center between 2020-2021 with T1–2 N0-1 M0, HR+, HER-2-negative disease were evaluated for histological type, tumor size, Nottingham grade, HR levels, Ki 67 expression (low < 10%, intermediate 10 ≥ Ki67 < 25 high ≥ 25), and Oncotype Dx RS(low <16,intermediate 16⩽RS<26), high ⩾26). Ki 67 and Oncotype Dx RS were treated as continuous variables to calculate a Pearson correlation coefficient. Results: Mean age at diagnosis was 59.4 years (range 48-89). Mean tumor diameter was 15.6 mm. 78.9% were intermediate histologic grade and 9.7% patients had lymph node involvement. Median expression of ER and PR were 90% (5-100) and 70% (0-100), respectively. The mean Ki 67 value was 17.5 (range 5-60 %), and mean Oncotype RS was 14.4 (range 4-34). There was a positive linear correlation between Ki 67 expression and Oncotype Dx RS (Pearson Correlation Coefficient=0.49, P-value <0.001). The vast majority of high Ki 67 pts (80%) had high/intermediate Oncotype RS. All pts with low Ki 67 (100%) had low/intermediate RS. Conclusions: Our community based rural cancer center data support a linear, statistically significant, positive correlation between Ki 67 and Oncotype Dx RS in early stage 0-3 node/HR+ positive breast cancer pts. Increasing use of Ki 67 testing in different clinical settings will generate more data to better define this correlation.[Table: see text]

Covariate clustering: Women with breast cancer in southwestern Paraná, Brazil

IntroductionDue to the high incidence and aggressiveness of breast cancer, understanding specific factors associated with the profile of the disease is necessary. Thus, the study aimed to analyze data from 155 patients with breast cancer, grouping them according to their clinicopathological characteristics, attended at a reference hospital for Oncology, in 2015–2020, in the southwest region of Paraná, Brazil. Material and MethodsUsing multivariate statistical analysis, sample data were divided into three clusters. The heterogeneity between clusters was obtained by Ward's method. The clinicopathological variables obtained from the patients' medical records were: the presence of intratumoral emboli and lymph nodes, menopausal status, molecular subtype, histological grade, TNM staging of the disease, tumor size, age at diagnóstico, weight, height, and body mass index. ResultsIt is observed that 70% of the patients were in menopause at diagnóstico, 31.5% had tumors containing emboli, and 41% had positive lymph nodes. The prevalence of Luminal B subtype, intermediate histological grade, and TNM staging II was verified. The prevalence of the disease was higher in women aged over 50 years, representing 66% of cases. The BMI of the patients ranged from 17.63 kg/m2 to 51.26 kg/m2, with 73.55% above 25 kg/m2. Using the spatial distribution of patients, cluster analysis identified the regions with the worst averages of clinicopathological variables and the highest number of cancer cases. ConclusionThrough the statistical analysis, it was possible to determine the heterogeneity of the data, so the patients were separated into three clusters. When analyzing the obtained clusters, each one of them had specific characteristics.

Impact of the EndoPredict genomic assay on treatment decisions for oestrogen receptor-positive early breast cancer patients: benefits of physician selective testing.

Genomic tests improve accuracy of risk prediction for early breast cancers but these are expensive. This study evaluated the clinical utility of EndoPredict®, in terms of impact on adjuvant therapy recommendations and identification of parameters to guide selective application. Patients with ER-positive, HER2-negative, and early-stage invasive breast cancer were tested with EndoPredict®. Two cohorts were recruited: one consecutively and another at clinical team discretion. Systemic treatment recommendations were recorded before and after EndoPredict® results were revealed to the multidisciplinary team. 233 patients were recruited across five sites: 123 consecutive and 110 at clinical team discretion. In the consecutive cohort 50.6% (62/123) cases were classified high risk of recurrence by EndoPredict®, compared with 62.7% (69/110) in the selective cohort. A change in treatment recommendation was significantly more likely (p < 0.0001) in the selective cohort (43/110, 39.1%) compared to the consecutive group (11/123, 8.9%). The strongest driver of selective recruitment was intermediate grade histology, whilst logistic regression modelling demonstrated that nodal status (p < 0.001), proliferative rate (p = 0.001), and progesterone receptor positivity (p < 0.001) were the strongest discriminators of risk. Whilst molecular risk can be predicted by traditional variables in a high proportion of cases, EndoPredict® had a greater impact on treatment decisions in those cases selected for testing at team discretion. This is indicative of the robust ability of the clinical team to identify cases most likely to benefit from testing, underscoring the value of genomic tests in the oncologists' tool kit.

EndoPredict\xae in early hormone receptor-positive, HER2-negative breast cancer

PurposeEvaluating consecutive early breast cancer patients, we analyzed both the impact of EndoPredict® on clinical decisions as well as clinico-pathological factors influencing the decision to perform this gene expression test.MethodsHormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative early breast cancer patients treated between 2011 and 2016 were included in this study to investigate the role of EndoPredict® (EPclin) in the treatment of early breast cancer. A main study aim was to analyze the changes in therapy recommendations with and without EPclin. In addition, the impact of clinico-pathological parameters for the decision to perform EPclin was examined by Pearson's chi-squared test (χ2-test) and Fisher's exact test as well as univariate and multivariate logistic regressions.ResultsIn a cohort of 869 consecutive early HR-positive, HER-negative breast cancer patients, EPclin was utilized in 156 (18.0%) patients. EPclin led to changes in therapy recommendations in 33.3% (n = 52), with both therapy escalation in 19.2% (n = 30) and de-escalation in 14.1% (n = 22). The clinico-pathological factors influencing the use of EPclin were age (P < 0.001, odds ratio [OR] 0.498), tumor size (P = 0.011, OR 0.071), nodal status (P = 0.021, OR 1.674), histological grade (P = 0.043, OR 0.432), and Ki-67 (P < 0.001, OR 3.599).ConclusionsEPclin led to a change in therapy recommendations in one third of the patients. Clinico-pathological parameters such as younger age, smaller tumor size, positive nodal status, intermediate histological grade and intermediate Ki-67 had a significant influence on the use of EndoPredict®.

TAILORx Update

TAILORx Update

Evaluation of Prognostic Factors for the Parotid Cancer Treated With Surgery and Postoperative Radiotherapy.

ObjectivesTo investigate the prognostic factors and treatment outcomes of primary parotid carcinoma treated with surgery and postoperative radiotherapy (PORT).MethodsWe reviewed retrospectively 57 patients with primary parotid carcinoma who were treated with surgery and PORT between 2005 and 2014. Superficial parotidectomy was performed in 19 patients, total parotidectomy in 10 patients, and total parotidectomy with lymph node dissection in 28 patients PORT on the tumor bed was performed in 41 patients, while PORT on tumor bed and ipsilateral cervical lymph nodes was performed in 16 patients.ResultsWith a median follow-up of 66 months, the 5-year overall survival, disease-free survival, locoregional control, and distant control rates were 77.0%, 60.2%, 77.6%, and 72.8%, respectively. The 5-year overall survival by stage was 100%, 100%, 80.0%, and 46.4% in stage I, II, III, and IV, respectively. Recurrences at primary lesions were found in seven patients, while at cervical nodes in six patients. Distant recurrences were developed in 12 patients. No patient with the low and intermediate histologic grade developed distant failure. As prognostic factors, the histologic grade for overall survival (P=0.005), pathological T-stage (P=0.009) and differentiation grade (P=0.009) for disease-free survival, pathological T-stage for locoregional control (P=0.007), and lympho-vascular invasion (P=0.023) for distant recurrence were significant on multivariate analysis.ConclusionThis study revealed that differentiation grade, histologic grade, pathological T-stage, and lympho-vascular invasion were significant independent prognostic factors on clinical outcomes.

The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements.

NTRK3-rearranged tumors other than infantile fibrosarcomas (IFSs) harboring the canonical ETV6-NTRK3 fusions are uncommon, and include mainly inflammatory myofibroblastic tumors and gastrointestinal stromal tumors. Herein, we describe an additional subset of seven tumors sharing NTRK3 gene rearrangements. The cohort included five females and two males (age range 1-67 years). Tumors were located in extremities, trunk, retroperitoneum, or intra-abdominal. In all tumors, fluorescence in situ hybridization (FISH) revealed rearrangements in NTRK3 accompanied by NTRK3 amplification in two cases. In three cases, RNA sequencing identified a fusion transcript composed of NTRK3 exon 14 fused to ETV6, TFG, and TPM4, respectively, retaining the NTRK3 kinase domain. All tumors were positive for pan-TRK by immunohistochemistry (IHC). Two cases showed low- to intermediate-grade histology composed of monomorphic spindle cells arranged in a patternless architecture, stromal bands, and perivascular rings of hyalinized collagen and coexpression of S100 and CD34. The remaining five cases were high-grade fascicular monomorphic spindle cell sarcomas, morphologically somewhat reminiscent of either malignant peripheral nerve sheath tumors (MPNSTs) or fibrosarcomas (FSs). Two high-grade NTRK3 sarcomas showed aggressive clinical behavior with development of lung metastases. Identification of high-grade NTRK3-rearranged sarcomas is clinically important, since the development of selective NTRK inhibitors has opened new avenues for targeted therapy. Although IHC for pan-TRK can be applied as a screening tool, molecular studies are recommended for a conclusive diagnosis of NTRK-rearranged neoplasms.

Are prostate cancer patients with BRCA1 and BRCA2 mutations safe for active surveillance?

19 Background: Active surveillance (AS) is recommended as a treatment option for men presenting with low risk (Gleason 3+3) and some intermediate risk (Gleason 3+4) prostate cancer. BRCA1 or 2 germline mutations have been implicated in prostate cancer pathogenesis. It is unknown if germline BRCA1/2 mutations in AS candidacy are associated with more aggressive histologic grade, higher stage or other worse genetic alterations, such as RB1 and p53 deletions. Methods: We analyzed sequencing data from 498 men who underwent radical prostatectomy from The Cancer Genome Atlas (TCGA) data set. The primary outcome was the difference in the proportions of AS candidates among subjects with and without BRCA homodeletions. Tests for differences in the proportions were conducted using Fisher’s Exact Test. Equivalence tests for proportions of AS candidates were conducted using the two-one sided tests (TOST) method. As a secondary outcome we studied the associated coincident mutations in the men with BRCA1 and BRCA2 homodeletions. Results: Forty-one men (8%) of the cohort had homodeletion of BRCA1 or BRCA2. Ten men (2%) had complete loss of BRCA1 while 31 (6%) had loss of BRCA2. Rates of candidacy for AS based on histology and stage (defined as stage T2, Gleason 6) are not different between subjects with and without BRCA 1 or 2 homodeletions, within an equivalence margin of 10 percentage points. These findings are similar when the AS criteria are modified to add Gleason 3+4 subjects. Fifty percent of men with organ confined (pT2), 3+3 and 3+4 prostate cancer with BRCA1 or BRCA2 homodeletions had concomitant RB1 deletions compared with 16.5% of the entire cohort (p = 0.002). This was primarily driven by BRCA2 deletions co-occurrent with RB1 deletions (log OR: 2.4, p &lt; 0.001). Twenty-nine percent of men from this group had concomitant p53 deletions compared to 7.5% of the entire cohort (p = 0.004). Conclusions: Men with prostate cancer and BRCA1 or BRCA2 homodeletions present with similar stage and grade tumors than men without these deletions. Despite having low or low intermediate grade histology, BRCA1 and BRCA2 deleted tumors are enriched with deletions in RB1 and TP53, both of which are associated with more aggressive phenotypes and treatment resistance.

Abstract P4-04-03: PIK3CA mutations in breast tumor specimens in a cohort (n=791) of a multicentric study and associations to known prognostic factors and survival data

Abstract Introduction: The PI3K/AKT/mTOR signalling pathway plays an important role in cellular processes like proliferation, apoptosis, survival and adhesion of tumor cells. It is one oft the most deregulated pathways in cancer. In up to 30% of breast cancers, dysregulation of this pathway is reported, resulting from mutations in the PIK3CA gene that encodes the catalytic subunit (p110a). Hotspots of mutations, comprising 86 % of all observed PIK3CA-mutations, were described in exon 9 (helical domain, E542K, G &amp;gt; A; E545K, G &amp;gt; A) and exon 20 (kinase domain, H1047R, A &amp;gt; G). Prevalence and the prognostic impact of the PIK3CA mutations as well as the predictive value with regard to endocrine therapy are controversially discussed. In this study we describe the prevalence of the three most frequent PIK3CA mutations in a consecutive cohort of breast cancer patients and its association to tumor characteristics, to known prognostic factors and survival data. Methods: The cohort consists of 1,047 patients who were newly diagnosed for non-metastatic breast cancer in one of 6 German breast centres from 2009 to 2011 and who were registered within the prospective PiA-study (Prognostic assessment in routine Application, NCT 01592825). DNA of 806 fresh frozen tumors were available for analyzation by qPCR (exon 9: C 763 and C760; exon 20: C 775). Associations between the PIK3CA mutation status and clinical, pathological parameters were evaluated using binary logistic regression model. Survival probabilities were estimated by Kaplan-Meier-method, Log-Rank-Test and Breslow-Test. Recurrence free interval (RFI) was defined according to STEEP criteria. Results: Mutation status for the three most common PIK3CA mutations was available for 791 tumors. The mutation rate was 29.2%. Only two tumors harbored two mutations (C 765, C 763). Tumors with a PIK3CA mutation were significantly more frequent in HR positive tumors (32%; p=0,001), in HER2 negative tumors (31%, p=0,010) and in tumors with low or intermediate histological grade (39%; 32% resp., each p&amp;lt;0,001). In triple negative tumors, PIK3CA mutations were found in 13%. There was no significant association to age, menopausal status, tumor size, nodal status and uPA/PAI-1 status. Tumors with a PIK3CA mutation showed a slightly better recurrence-free interval (93.6%, CI 93.2-94.01 vs. 90.3%, CI 89.9-90.7). We found a prognostic impact on RFI after 5 ys F/U in patients with HR-negative tumors (93% vs 71%) and those with TNBC (100% vs. 70%). Conclusion: PIK3CA mutations occur frequently in breast cancer tumors. We found a prognostic impact only in patients with HR-negative and TNBC tumors. This data adds important information to the heterogeneous results of other previously published patient cohorts. In summary in our study, tumors that harbour a mutation of the PIK3CA-gene, were associated to prognostically more favorable factors and a better recurrence-free intervall. Citation Format: Reinhardt K, Thomssen C, Volker H, Tilmann L, Christoph U, Susanne P, Jutta J, Joerg B, Edith W, Karl-Friedrich B, Eva Johanna K, Martina V. PIK3CA mutations in breast tumor specimens in a cohort (n=791) of a multicentric study and associations to known prognostic factors and survival data [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 P4-04-03.

Abstract P3-08-22: Oncotype Dx recurrence score risk groups according to Ki67, a predictor to be considered

Abstract Background The gene expression profiling assay OncotypeDx (ODx) prognosticates the risk of estrogen receptor positive (ER+) breast cancer (BC) recurrence and assesses the likely benefit from adjuvant chemotherapy in addition to endocrine therapy. There have been several attempts to develop algorithms that provide similar outcome prediction to the ODx assay with the use of routine clinicopathological characteristics. Ki67 is frequently incorporated into these assessments, although there is no standard cut-off for its use. Methods We retrospectively reviewed the electronic medical records of 330 patients with early stage ER+ BC for whom ODx recurrence score (RS) was available. Patients were diagnosed and treated at two specialized cancer centers between 2014 and 2017. Our objective was to determine the ki67's median differences between ODx risk groups. We used Spearman rho for the correlation between Ki67 and ODx score and used Kruskal-Wallis test for compare medians, pairwaise comparison for the intergroup relations. Results Mean age at diagnosis was 57.42 years (range 28-89). Mean tumor diameter was 15.67 mm. 78.9% were intermediate histologic grade and 9.7% patients had lymph node involvement. Median expression of ER and PR were 90% (5-100) and 70% (0-100), respectively. We assessed the correlation between Ki67 and ODx score, with a pearson r:0.31, p&amp;lt;0.001. The data showed a directly proportional trend between Ki67 and ODx score. Median Ki67 was 20 (1-100). According to ODX RS, 61.5% of tumors were low risk, 30.3% were intermediate risk and, 8.2% were high risk. Median Ki67 within each category group is as follows: low: 15 (IQR:15), intermediate: 20 (IQR:18) and high: 40 (IQR:35), with a statistically significant difference between medians (p&amp;lt;0.001). In the Pairwise comparison intergroup the data showed: Low-Intermediate (p&amp;lt;0.05), Low-High (p&amp;lt;0.001), Intermediate-High (p&amp;lt;0.001). Conclusions The data showed directly proportional trend between Ki67 and ODx score. In our population there is a statistically significant difference between Ki67 medians according to ODx risk groups. Citation Format: Namuche F, Ruiz R, Morante Z, Aguilar A, Gomez H. Oncotype Dx recurrence score risk groups according to Ki67, a predictor to be considered [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 P3-08-22.

Abstract P3-08-17: Evaluation of Oncotype DX testing and subsequent treatment choices in the Latin American setting

Abstract Background: The gene expression profiling assay OncotypeDx (ODx) prognosticates the risk of estrogen receptor positive (ER+) breast cancer (BC) recurrence and assesses the likely benefit from adjuvant chemotherapy in addition to endocrine therapy. Numerous clinical utility studies have shown that acknowledging the RS impacts on clinical decision making, leading to a decrease in chemotherapy (CT) use. However, the cost of the assay limits it widespread use, especially in low and middle-income countries. Our objective was to determine the patterns of use of ODx, its results and the subsequent treatment choices in a large Latin American cohort. Methods: We retrospectively reviewed the electronic medical records of patients with early-stage ER+ BC for whom ODx recurrence score (RS) was available. Patients were diagnosed and treated at 3 specialized Peruvian cancer centers between 2007 and 2017. Descriptive results for numeric variables were presented as means with standard deviation (SD) or medians with interquartile range (IQR), depending on their distributions; otherwise, we expressed the qualitative variables as numbers with percentages. We evaluated the association between ODx RS category and treatment using the Chi-squared test. Results: A total of 551 patients were included. Patients had a mean age of 56.2 ± 11.9 (SD) (range: 26-89). 9.6% (n=53) of patients were ≤40 years old. The size of the tumors ranged from 0.1 cm to 7.2 cm (median = 1.5 cm; IQR 1.0-2.2cm). 36 (6.5%) patients had tumors ≤ 0.5cm and 7 (1%) had tumors &amp;gt; 5cm. A minority of patients had lymph node involvement (5.8%, n=32). ODx was ordered in 55 cases (10%) of lobular carcinoma and in 23 cases (4%) of favorable histology tumors (19 mucinous, 4 tubular). Most tumors exhibited an intermediate histological grade (71.6%, n=386). Ki67 was available in 58.8% patients (n= 324), with a median Ki67 of 20 (IQR 10-30). Using commercial cutoffs RS was distributed as follows: low (0–17) = 316 (57.4%), intermediate (18–30) = 177 (32.1%), and high (≥31) = 58 (10.5%). In general, 57.5% (n=317) of patients received endocrine therapy (ET) as their only systemic treatment and 42.5% (n=234), also received CT (ET + CT). In the low-risk category, 87.3% (n=276) of patients received ET and 12.7% (n=40), ET + CT. Within the intermediate-risk category, most patients received ET + CT (77.4%, n=137). Only one patient in the high-risk category did not receive CT. There was a significant association between the RS group and treatment choice (p&amp;lt;0.001). Impact of ODx RS results on treatment recommendations Oncotype risk categories LowIntermediateHighp valueTreatmentn%n%n%&amp;lt;0.001Endocrine therapy27687.34022.611.7 Chemotherapy + Endocrine therapy4012.713777.45798.3 Conclusion: ODx significantly influenced treatment decisions in our cohort, however an overutilization of CT was found in low-risk patients. Further data analysis is needed to explain the higher than expected use of CT. Also, there is room for improvement in the selection of cases that undergo ODx testing. Citation Format: Ruiz R, Morante Z, Namuche F, Urrunaga D, Aguilar A, Schwarz J, Leon M, Ziegler G, Chavez Mac Gregor M, Gomez H. Evaluation of Oncotype DX testing and subsequent treatment choices in the Latin American setting [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 P3-08-17.

Abstract P3-08-18: Clinicopathological characteristics associated with intermediate and high-risk ODx RS

Abstract Background: The gene expression profiling assay OncotypeDx (ODx) prognosticates the risk of estrogen receptor positive (ER+) breast cancer (BC) recurrence and assesses the likely benefit from adjuvant chemotherapy in addition to endocrine therapy. There have been several attempts to develop algorithms that provide similar outcome prediction to the ODx assay with the use of routine clinicopathological characteristics. These models appear to predict high-risk ODx RS but are unable to reliably rule out the presence of patients with intermediate-risk disease. Our objective was to identify the clinicopathological factors associated with intermediate and high-risk categories. Methods: We retrospectively reviewed the electronic medical records of patients with early-stage ER+ BC for whom ODx recurrence score (RS) was available. Patients were diagnosed and treated at 3 specialized cancer centers between 2010 and 2017. Two multinomial logistic regression models (crude and adjusted) were constructed to assess the association between clinicopathological characteristics and ODx RS as a categorical variable. The adjusted model included the following variables: ODx RS, age, tumor size, node status, grade, lymphovascular invasion and hormonal receptors. The reported association measure was the relative prevalence ratio (RPR) with its respective 95%CI. Results: A total of 551 patients were included. Patients had a mean age of 56.2 ± 11.9 (SD) (range: 26-89). 9.6% (n=53) of patients were≤40 years old.The size of the tumors ranged from 0.1 cm to 7.2 cm (median = 1.5 cm; IQR 1.0-2.2cm). A minority of patients had lymph node involvement (5.8%, n=32). By subtype, carcinomas were mostly ductal (83.5%, n=460), followed by lobular (10.0%, n=55) and mucinous (3.5%, n=19). The majority of tumor exhibited an intermediate histological grade (71.6%, n=386). Ki 67 was available in 58.8% patients (n= 324), with a median Ki67 of 20 (IQR 10-30). In the adjusted multinomial logistic regression model, factors associated with ODx intermediate-risk category were grade 3 (RPR=4.78; 95%CI: 2.01-11.39) and having either ER or PR &amp;lt;50 (RPR=2.80; 95%CI: 1.83-4.27). Factors associated with ODx high-risk category were grade 3 (RPR=15.89; 95%CI: 3.23-78.19), having either ER or PR &amp;lt;50 (RPR=4.58; 95%CI: 2.37-8.87), age≤40 (RPR=2.96; 95%CI: 1.20-7.29) and T2-3 (RPR=2.20; 95%CI: 1.13-4.32). Conclusion: Grade 3, ER o PR &amp;lt;50, age ≤40 years and T2-3 are clinicopathological characteristics strongly associated with high-risk ODx RS. The associations with intermediate-risk ODx RS are weaker. The way these factors could be integrated into a clinicopathologic risk prediction model to identify high-risk patients needs further analysis. Citation Format: Ruiz R, Morante Z, Namuche F, Urrunaga D, Leon M, Ziegler G, Aguilar A, Chavez Mac Gregor M, Gomez H. Clinicopathological characteristics associated with intermediate and high-risk ODx RS [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 P3-08-18.

Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.

The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.

P1.16-64 The Histological Predominant Pattern Could Predict Site of Recurrence and Metastasis in Surgically Treated Stage I Adenocarcinoma of the Lung

Pattern-based subtyping of adenocarcinoma of the lung is currently recommended due to prognostic implications. We aimed to evaluate whether predominant pattern subtype in surgically treated stage I adenocarcinoma of the lung can predict first site of recurrence or metastasis. We retrospectively reviewed clinical information, radiological findings, PET/CT-records, and pathological features (classified by IASLC/ATS/ERS subtyping criteria) of 906 Stage-I adenocarcinoma of the lung, who underwent surgery in 7 Centers. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification as follow: intermediate grade (Invasive Lepidic, Acinar, Papillary) vs. high grade (Micropapillary, Solid) vs. NOS. The date of recurrence or metastases was defined as the first radiographic evidence of cancer relapse upon imaging or pathological tumour evidence from a biopsy. Univariate and multivariate logistic analysis were used to identify predictors of first site of recurrence or metastasis. A total of 248 (27%) patients developed recurrence or distant metastasis. The most commonly observed first location of recurrence was ipsilateral thorax (133 cases, 44%), followed by brain (27, 11%), contralateral lung (24, 10%), bones (11, 4%), liver and adrenal gland (10, 4%). Forty-three patients (17%) presented recurrence or metastasis in multiple sites simultaneously at the time of diagnosis. At multivariate analysis, patients with intermediate-grade histology developed intra-thoracic recurrence more frequently compared to the remainder of the cohort (odds ratio (OR) 1.85, 95% confidence interval (CI): 1.1– 3.18, P=0.038). Patients with high-grade histology developed contralateral lung metastasis (OR 2.1, 95%CI 1.1-4.2, P= 0.044) and brain metastasis (OR 2.5, 95%CI 1.3-5.1, P<0.01) more frequently compared to the low-grade ones. Predominant pattern subtype seems to predict site-specific recurrence and metastasis in surgically treated Stage I adenocarcinoma of the lung.

Clinical utility of dynamic-enhanced MRI in salivary gland tumors: retrospective study and literature review.

To improve the diagnoses of the salivary gland tumors, a dynamic-enhanced MRI (dMRI) was investigated. We conducted a retrospective chart review of 93 cases of salivary gland tumors. The histological diagnoses were obtained from all patients using a surgical specimen and/or an open biopsy specimen. The dMRI as well as fine-needle aspiration cytology (FNAC) and intraoperative frozen section (IFS) were analyzed. This study focused on the time-intensity curve (TIC) after injection, peak time (Tpeak), washout ratio (WR) as well as the gradient of enhancement and washout profile. The histological diagnoses included pleomorphic adenoma (PMA) in 53 cases, the Warthin tumors (WT) in 14 cases and malignant tumors (MT) in 26 cases. Incorrect diagnosis rate of FNAC and IFS were 5.2 and 8.3%, respectively. The TIC revealed differences among the three types of tumors. Tpeak as well as WR also revealed significant differences (p < 0.001). Tpeak were lower in order of WT, MT, PMA, respectively. WR of TICs at 30, 45 and 105s after Tpeak were higher in order of WT, MT, PMA, respectively (p < 0.001). The gradient of increment and washout in the TIC curve was also an important parameter to distinguish the three types of tumors. In MT, the rapid enhancement pattern was found in high or intermediate histological grade tumors, whereas the slow enhancement pattern was exhibited in low grade tumors. Our findings indicate that using Tpeak and WR, it is possible to distinguish between WT, PMA and MT. Additionally, a rapid enhancement pattern may be a potential marker for these tumors.

Abstract P2-09-25: Clinical and pathologic characteristics of breast cancers determined to be HER2-positive by fluorescence in-situ hybridization (FISH) using alternative chromosome 17 probes

Abstract Background: Based on updated 2013 ASCO/CAP guideline for HER2 testing, cases with a HER2/CEP17 ratio &amp;lt; 2.0 but with an average HER2 copy number &amp;gt; 4.0 and &amp;lt;6.0 signals/cell are considered equivocal. In such cases, HER2 testing using alternative chromosome 17 probes was proposed as one way to resolve the equivocal FISH results. Using the alternative probe method increases the number of cancers categorized as HER2 positive but brings to question if these cancers truly represent HER2 amplified breast cancers and derive the same benefit from anti-HER2 therapies. Methods: Since 2013, all breast cancers at our institution that were HER2 equivocal by traditional FISH but classified as HER2 positive using the alternative probe method were assessed for clinical and pathologic features including histologic type and grade, TNM stage, HER2: alternative probe ratio, treatment, and clinical outcome. Results: We identified 24 invasive breast cancers considered HER2 positive by the alternative probe method: 23 (96%) were estrogen receptor-positive (ER+) and 20 (83%) were progesterone receptor- positive. Histologically, only 2 were invasive lobular carcinomas; all others were ductal or had ductal and lobular features. Most cancers (63%) had low or intermediate histologic grade: Grade 1 (n=3); Grade 2 (n=12); Grade 3 (n=9). Clinical information was available for 18 patients: 2 had metastatic disease, 1 had a local recurrence after mastectomy and 15 patients had early stage disease; 9 with node negative disease and 6 with nodal involvement. HER2 IHC was equivocal (2+) in 16 (66.7%) cases, positive (3+) in 4 (16.7%) cases, and negative (0 or 1+) in 4 (16.7%) cases. The average HER2 copy number was 4.77, the average HER22:p53 ratio was 2.61. Repeat HER2 testing on a 2nd tumor sample was performed in 8 cases: HER2-positivity was confirmed in only 2 (25%) cases and by the alternative probe only. Treatment information was available for 17 patients: 1 had T1aN0M0 lesion and did not get chemotherapy, 16 received chemotherapy and 13 received trastuzumab-based chemotherapy. Eleven patients with early stage disease received chemotherapy and trastuzumab. Of these patients, 10/11 were ER+, 7/11 were node negative and 5/11 had grade 2 tumors, yet only one tumor was assessed by oncotype recurrence score ( RS = 29). Three patients received chemotherapy and trastuzumab in the neoadjuvant setting: 1 had a complete pathologic response, 1 a partial response, and 1 has not yet gone to surgery. One additional patient received neoadjuvant chemo alone and achieved a partial response. Conclusions: Breast cancers considered HER2+ by the alternative probe method but not by traditional FISH are almost always ER-positive and most have low or intermediate histologic grade. Repeat HER2 testing on a subsequent tumor sample did not confirm HER2-positivity in 75% of cases. Almost all patients with early stage disease received chemotherapy and trastuzumab based on the alternative probe results without molecular assessment to predict chemotherapy response. Intrinsic molecular subtyping using PAM50 analysis on these cancers is underway to determine how many are HER2-enriched by molecular assessment. Citation Format: Desai NV, Torous V, Cruz C, Schnitt SJ, Tung N. Clinical and pathologic characteristics of breast cancers determined to be HER2-positive by fluorescence in-situ hybridization (FISH) using alternative chromosome 17 probes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-25.

Retroperitoneal dedifferentiated liposarcoma: Analysis of 61 cases from a large institution.

Background: To describe the clinical features of retroperitoneal dedifferentiated liposarcoma (RP DDLS) and further evaluate the prognostic factors.Methods: The clinicopathological variables and treatment strategies of 61 RP DDLS patients who underwent surgical resections at a single institution between September 2005 and September 2016 were reviewed. Kaplan-Meier and Cox regression methods were conducted for survival analyses.Results: The average patients' age was 52 years (range, 27-81), and there was almost no gender predilection (30 males vs. 31 females). 51 (83.6%) patients got gross tumor resections (R0/R1 resection), and the median tumor size was 19 cm (range, 4.3-50 cm). 39(63.9%) patients were with intermediate-grade sarcoma and 22(36.1%) were with high-grade sarcoma. The median intraoperative blood loss was 400 ml (range, 50-2700ml). 19 (31.1%) patients presented multifocal diseases. Tumors were removed intactly in 42 (68.9%) patients. In order to obtain gross tumor resections, 33 (54.1%) of the patients underwent excisions of at least one adjacent organ, of which kidney (n=21, 63.6%) was the most common one. 6 (9.8%) patients developed distant metastases during follow-up. The overall 5-year progression-free survival (PFS) rate was 3.7%, with the median PFS of 19 months. The 5-year overall survival (OS) rate was 43.5%, with the median OS of 58 months. Updating to November 2017, 30 (49.2%) patients remained alive. The median follow-up time was 49 months. Multivariate analysis using Cox proportional hazards model revealed that tumor grade, blood loss, resection extent, and tumor integrity were independently associated with OS (p=0.032, p=0.018, p=0.020, p=0.005, respectively). Tumor grade, tumor integrity and multifocality were significant predictors for PFS (p=0.013, p=0.080, p=0.009, p=0.028, respectively).Conclusion: Intermediate-grade histology, intraoperative blood loss < 400 ml, complete tumor resection, and tumor integrity were independently associated with better OS. Intermediate-grade histology, tumor integrity and unifocal disease independently predicted favorable PFS.

Carcinome mucineux du sein : profil clinique, biologique et évolutif

PurposeMucinous carcinoma of the breast accounts for 1 to 4% of all breast cancer. There are two histological subtypes: mixed mucinous carcinoma, where the ductal carcinoma is associated with the colloid component, and pure mucinous carcinoma, with a favorable prognosis, where the mucus surrounds the tumour tissue and constitutes a mechanical barrier limiting cell invasion and making this form less aggressive. Our study aimed to determine retrospectively the main epidemiological, clinical, biological, and therapeutic features, as well as the prognosis of this rare form of breast carcinoma. Materials and methodsThe authors report 32 cases of mucinous carcinoma of the breast diagnosed in Mohammed-VI centre for cancer treatment in Casablanca. ResultsThe average tumour size was 4.5cm (0.5–7cm). We found ten positive lymph node dissections, seven of them were of mixed mucinous carcinoma with a tumour size ranging between 4 and 7cm. Mucinous carcinoma was pure in 16 cases, mixed in 14 and a neuroendocrine differentiation was found in two cases. Most tumours were of an intermediate histological grade (n=19) with positive hormonal receptors (68%). After a mean follow-up of 30 months, complete remission was maintained in 92% of evaluable patients. ConclusionMucinous carcinoma is a rare type of breast cancer, with a favourable prognosis for the pure form.