Indication For Adjuvant Chemotherapy Research Articles

Comparison of unsupervised machine-learning methods to identify metabolomic signatures in patients with localized breast cancer

Genomics and transcriptomics have led to the widely-used molecular classification of breast cancer (BC). However, heterogeneous biological behaviors persist within breast cancer subtypes. Metabolomics is a rapidly-expanding field of study dedicated to cellular metabolisms affected by the environment. The aim of this study was to compare metabolomic signatures of BC obtained by 5 different unsupervised machine learning (ML) methods. Fifty-two consecutive patients with BC with an indication for adjuvant chemotherapy between 2013 and 2016 were retrospectively included. We performed metabolomic profiling of tumor resection samples using liquid chromatography-mass spectrometry. Here, four hundred and forty-nine identified metabolites were selected for further analysis. Clusters obtained using 5 unsupervised ML methods (PCA k-means, sparse k-means, spectral clustering, SIMLR and k-sparse) were compared in terms of clinical and biological characteristics. With an optimal partitioning parameter k = 3, the five methods identified three prognosis groups of patients (favorable, intermediate, unfavorable) with different clinical and biological profiles. SIMLR and K-sparse methods were the most effective techniques in terms of clustering. In-silico survival analysis revealed a significant difference for 5-year predicted OS between the 3 clusters. Further pathway analysis using the 449 selected metabolites showed significant differences in amino acid and glucose metabolism between BC histologic subtypes. Our results provide proof-of-concept for the use of unsupervised ML metabolomics enabling stratification and personalized management of BC patients. The design of novel computational methods incorporating ML and bioinformatics techniques should make available tools particularly suited to improving the outcome of cancer treatment and reducing cancer-related mortalities.

209P - Influence of age on the indication of adjuvant chemotherapy in early breast cancer using Oncotype DX. An analysis of 240 patients treated in the Institut Catala d’Oncologia (ICO) hospitals

BackgroundBenefit derived from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients (pt) with hormone-receptor–positive HER2 negative early breast cancer. The 21-gene recurrence-score (RS) assay Oncotype DX, provide prognostic and predictive information. Results of the TAYLORx study have confirmed that most of patients with negative node status and RS>25 can avoid CT without increasing their risk of relapse. However, pt<50 years (y) and RS>20 showed benefit with CT. MethodsAim: To analyse the impact of age using RS test to change the indication of adjuvant CT and the relationship between different clinical pathological factors and the RS value. We analysed 240 cases out of 251 RS test performed in the 3 ICO Centers during 2017-2018. We compared the adjuvant treatment initially planned according to institutional protocol with the treatment given after RS in the total cohort and in pt<50 y. We performed a logistical regression analysis of pathological factors and RS. ResultsCT was indicated in all pt before knowing the RS results. Only 46pt (19%) received CT after RS results. 14 out of 88pt < 50 y received adjuvant CT (15%). 15pt <50 y had a RS between 21-25, only 5 of them received CT, because in most of them, the RS was performed prior TAILORx results were published. Nowadays, all of these 15pt would had received CT: 61/240 (25%). Clinical-pathological characteristics of the series are summarized in the Table. Of the risk factors analysed, only Ki67>25 (<0.001) and PR≤20% (0.01) showed a statistically significant relationship with a higher probability of RS>25 in a multivariate analysis.Table209PTableAge median (range)53 (19-76) <50 y 35.1% ≥50 y 64.9%Tumor size median15mmHistological gradeG1 23% G2 69.7% G3 4.4%Progesterone receptor≤20% 21% >20% 78%Ki67 median (p25-75)20 (13,28) ≤14 27% 14-25 41% >25% 31%Nodal statuspN0 57%pN1mic 15%pN1a 27% Conclusions82% of pt of our series could avoid CT, however this proportion change after TAYLORx results in younger patients. Today 75% of these pt would had avoided CT. Ki67 > 25% and Progesterone Receptor ≤20% were the only pathological factors associated with an increased risk of RS>25. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract 2449: Unsupervised machine learning methods reveal metabolomic based clusters in breast cancer patients

Abstract Background Transcriptomic have led to the now widely used sub-type based classification of breast cancer first described by Perou in 2000. Yet there persists heterogeneity in biological behaviors within breast cancer subtypes, underlining the need to refine the taxonomy of breast cancer. Metabolomics is a rapidly expanding field dedicated to the study of metabolism which integrates the impact of the environment on cell biology. The aim of this study was to identify new biological breast cancer clusters using different unsupervised machine learning (ML) methods based on metabolomic features. Those methods, in which no a priori class label information is given to guide the algorithm, seem suitable to address this type of problem. Methods 52 patients with breast cancer and an indication for adjuvant chemotherapy between 2013 and 2016, were retrospectively included. Tumor resection specimens were analyzed. 1300 metabolomic were extracted by combined liquid chromatography-mass spectroscopy and processed using MZmine software and the “Human Metabolome” database. 5 unsupervised ML methods were used: PCA-Kmeans, Sparcl, SIMLR, Spectral clustering and K-sparse. Clinical differences between clusters and variations for every metabolite of interest were analyzed for each clustering method. Cluster separability and homogeneity was evaluated using the silhouettes method and t-sne visual evaluation. Results Among the 5 clustering methods, with a partitioning optimum parameter k=3, only K-sparse and SIMLR methods generated 3 clusters with significant clinical differences, unmatched to traditional subtypes. These differences concerned: tumor stage, axillary lymph node invasion, histological grade, ki-67 proliferation index, and tumor phenotype. With a silhouette average of 0.84 and 0.85 for K-sparse and SIMLR methods respectively, those 2 methods gave the best score in terms of silhouette average and they showed a better gradient for tumor aggressiveness compared to the 3 other methods. Among them, 42 and 55 metabolites were selected for the construction of tumor metabolome profiles for K-sparse and SIMLR, respectively. Among selected metabolites we found a significant increase of L-methionine, L-phenylalanine, L-isoleucine and L-proline along with a significant decrease in glutathione (also characteristic of oxidative stress) and glutamate in the cluster associated with poorer histopronostic factors. This high concentration of proteinogenic amino-acid and low concentration of amino-acid precursors could be correlated to poorer prognosis. Conclusion Unsupervised ML methods generate heterogeneous results when applied to metabolomics data extracted from breast cancer patients. K-sparse and SIMLR were able to identify three different groups based on tumor metabolome. Tumors with the worst histopronostic factors seemed to present higher concentrations of protienogenic amino-acids. Note: This abstract was not presented at the meeting. Citation Format: Jocelyn Gal, Caroline Bailleux, David Chardin, Thierry Pourcher, Lun Jing, Jean-Marie Guignonis, Jean-Marc Ferrero, Renaud Schiappa, Emmanuel Chamorey, Olivier Humbert. Unsupervised machine learning methods reveal metabolomic based clusters in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2449.

Budget Impact Analysis of Molecular Lymph Node Staging Versus Conventional Histopathology Staging in Colorectal Carcinoma.

BackgroundThe presence of lymph node (LN) metastasis is a critical prognostic factor in colorectal cancer (CRC) patients and is also an indicator for adjuvant chemotherapy. The gold standard (GS) technique for LN diagnosis and staging is based on the analysis of haematoxylin and eosin (H&E)-stained slides, but its sensitivity is low. As a result, patients may not be properly diagnosed and some may have local recurrence or distant metastases after curative-intent surgery. Many of these diagnostic and treatment problems could be avoided if the one-step nucleic acid amplification assay (OSNA) was used rather than the GS technique. OSNA is a fast, automated, standardised, highly sensitive, quantitative technique for detecting LN metastases.ObjectivesThe aim of this study was to assess the budget impact of introducing OSNA LN analysis in early-stage CRC patients in the Spanish National Health System (NHS).MethodsA budget impact analysis comparing two scenarios (GS vs. OSNA) was developed within the Spanish NHS framework over a 3-year time frame (2017–2019). The patient population consisted of newly diagnosed CRC patients undergoing surgical treatment, and the following costs were included: initial surgery, pathological diagnosis, staging, follow-up expenses, systemic treatment and surgery after recurrence. One- and two-way sensitivity analyses were performed.ResultsUsing OSNA instead of the GS would have saved €1,509,182, €6,854,501 and €10,814,082 during the first, second and third years of the analysis, respectively, because patients incur additional costs in later years, leading to savings of more than €19 million for the NHS over the 3-year time horizon.ConclusionsIntroducing OSNA in CRC LN analysis may represent not only an economic benefit for the NHS but also a clinical benefit for CRC patients since a more accurate staging could be performed, thus avoiding unnecessary treatments.Electronic supplementary materialThe online version of this article (10.1007/s40258-019-00482-7) contains supplementary material, which is available to authorized users.

Significant inter- and intra-laboratory variation in grading of invasive breast cancer: A nationwide study of 33,043 patients in the Netherlands.

Accurate, consistent and reproducible grading by pathologists is of key‐importance for identification of individual patients with invasive breast cancer (IBC) that will or will not benefit from adjuvant systemic treatment. We studied the laboratory‐specific grading variation using nationwide real‐life data to create insight and awareness in grading variation. Synoptic pathology reports of all IBC resection‐specimens, obtained between 2013 and 2016, were retrieved from the nationwide Dutch Pathology Registry (PALGA). Absolute differences in laboratory‐proportions of Grades I–III were compared to the national reference. Multivariable logistic regression provided laboratory‐specific odds ratios (ORs) for high‐ vs. low‐grade IBC. 33,792 IBC pathology reports of 33,043 patients from 39 laboratories were included, of which 28.1% were reported as Grade I (range between laboratories 16.3–43.3%), 47.6% as Grade II (38.4–57.8%), and 24.3% as Grade III (15.5–34.3%). Based on national guidelines, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. After case‐mix correction, 20 laboratories (51.3%) showed a significantly deviant OR. Significant grading differences were also observed among pathologists within laboratories. In this cohort of 33,043 breast cancer patients, we observed substantial inter‐ and intra‐laboratory variation in histologic grading. It can be anticipated that this has influenced outcome including exposure to unnecessary toxicity, since choice of adjuvant chemotherapy was dependent on grade in nearly a third of patients. Better standardization and training seems warranted.

Abstract P5-15-09: Impact of oncotype dx genetic signature used in early breast cancer. Clinical and economic analisys of a 110 patient cohort treated in the Catalan Oncologic Institute (ICO), Spain

Abstract Introduction Benefit from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients with early breast cancer. The 21-gene recurrence-score (RS) assay (Oncotype DX, Genomic Health) is one gene-expression assay that provide prognostic and predictive information in hormone-receptor (RH) positive breast cancer. The results of the TAILORx study have confirmed that the majority of patients with tumors RH + and HER2 negative can avoid CT without increasing their risk of relapse. From 2012 to 2015 we used Mammaprint (MMP), in our institution and 60% of cases could avoided CT (communicated in SABCS 2015). Since 2017 we use RS for this purpose. Primary Objective To analyze the impact of using RS to change the indication of adjuvant CT. Secondary Objectives To analyze the association between different clinical pathological factors and the RS value, and calculate the difference between the cost of all RS test and the cost in direct expense of the treatment with CT of all patients who could avoid it thanks to the RS Material and methods We analyzed all RS test performed in the three ICO centers during 2017. We sent 112 tumor samples; in 2 samples adequated RNA for RS was not obtained. We compared the adjuvant treatment initially planned according to institutional treatment protocol with the treatment given after RS. We compared the direct economic costs of CT with the costs of the diagnostic test, and performed a logistic regression analysis of some pathological factors and RS value. Results The RS could be determined in 110 of 112 cases, in which there was indication of adjuvant CT. Only 14 patients received CT (12,72%) with the RS value, so CT was avoided in 96 patients (87,28%). The clinical-pathological characteristics of the series are summarized in the table 1. Of the risk factors analyzed, only grade 3 (p 0.001) and PR &amp;lt;20% (p&amp;lt;0.002) showed a statistically significant relationship with a higher probability of RS&amp;gt; 25. No association was found between age, nodal status, tumor diameter, Ki67, Infiltrating Ductal Carcinoma vs neither Infiltrating Lobular Carcinoma nor Lympho-Vascular invasion. The cost of the genetic studies was 180000€ (1636€ each). The cost of each CT schedule (EC x 4 followed by paclitaxel x 12) was 7214€ and the total cost of 96 cases 692590€. Direct costs savings estimated from the reduction in CT treatment were 512590€ Conclusion: Our series shows that RS avoided unnecessary CT in 87% of cases and was more cost-effective than a previous series with MMP. G3 and RP &amp;lt;20 were the only pathological factors associated with an increased risk of RS&amp;gt; 25. Table 1.Patients characteristics and clinical-pathological details from the analyzed tumorsPatient characteristicsAge, mean (range)53,76 (19 – 75)≥50y72 (65.5%)&amp;lt;50y38 (34.5%)HistologyInfiltrating ductal carcinoma88 (80%)Infiltrating lobular carcinoma20 (18,2%)Others2 (1,8%)TNMTumor diameter (mm), mean (range)19,25 (1 – 160)pN058 (52,7%)pN1mic21 (19%)pN131 (28,3%)Hormone receptorsRE 2-100%110 (100%)RP &amp;lt;20%22 (20%)RP ≥20%88 (80%)Ki67 median, mean (range)20, 21 (2-75)Lymphovascular invasionyes9 (8%)no101 (92%)Adjuvant treatmentCT14 (12,72%)Hormonotherapy96 (87,28%) Citation Format: Ferrer M, Dorcas J, Quiroga V, Margelí M, del Barco S, Stradella A, Petit A, Falo C, Viñas G, Romeo M, Villanueva R, Cirauqui B, Vázquez S, Fernández A, Recalde S, Vethencourt A, Soler T, Pérez-Martín X, Gil-Gil M. Impact of oncotype dx genetic signature used in early breast cancer. Clinical and economic analisys of a 110 patient cohort treated in the Catalan Oncologic Institute (ICO), Spain [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 P5-15-09.

Abstract P4-02-13: Inter- and intra-laboratory variation in grading of invasive breast cancer: A nationwide study in the Netherlands

Abstract Background Histologic grading is one of the best established prognostic factors in invasive breast cancer (IBC) and is used to guide patient management. Yet, the level of inter- and intra-observer agreement does not reach high enough clinical standards. To improve standardization, we aimed to gain insight into laboratory-specific variation in histologic grading. Methods All synoptic pathology reports of IBC resection specimens between 2013-2016 were retrieved from PALGA, the nationwide Dutch Pathology Registry. All lesions were graded according to the modified Bloom and Richardson guideline, which combines assessment of cell morphology (nuclear polymorphism), measurement of differentiation (tubular differentiation) and assessment of proliferation (mitotic count). Absolute differences in proportions of grade I-III and the three components of grading between laboratories were compared to the national distributions. For logistic regression analyses, grade was dichotomized into high- and low-grade by two alternative definitions for high-grade IBC (either solely grade III or grade II-III). Multivariable logistic regression, to correct for case mix (age, tumor size, type of surgery, histologic subtype, ER/PR-receptor status, HER2-receptor status), provided two laboratory-specific odds ratios (ORs) and 95% confidence intervals (CI) for high versus low-grade IBC compared to the reference laboratory. Findings In total 33.792 IBC cases from 39 laboratories were included, of which 28.1% were reported as grade I (range 16.3-43.3%), 47.6% as grade II (range 38.4-57.8%), and 24.3% as grade III (range 15.5-34.3%). More than half of the laboratories (22/39) showed proportions outside the 95% confidence limits of the national proportion for both grade I and grade III, followed by 41.0% of the laboratories for grade II. After case mix correction, 20 laboratories (51.3%) showed at least one significantly higher or lower OR than the reference laboratory. Four laboratories (10.3%) showed significantly deviant ORs on both analyses. Most variation between laboratories was observed for nuclear polymorphism. Significant grading differences were also observed between pathologists within 62.5% of the laboratories that could be analyzed. Overall, the indication for adjuvant chemotherapy was dependent on histologic grade in 29.9% of patients. Conclusion We observed substantial inter- and intra-laboratory variation in the histologic grading of IBC, which may likely influence treatment decisions and subsequently patient outcome as the indication for chemotherapy depends on histologic grade in almost every one in three patients. Citation Format: van Dooijeweert C, van Diest PJ, Willems SM, Kuijpers CC, Overbeek LI, Deckers IA. Inter- and intra-laboratory variation in grading of invasive breast cancer: A nationwide study in the Netherlands [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 P4-02-13.

Significance of perineural and lymphovascular invasion in locally advanced rectal cancer treated by preoperative chemoradiotherapy and radical surgery: Can perineural invasion be an indication of adjuvant chemotherapy?

PurposeTo investigate the prognostic significance of lymphovascular space invasion (LVI) and perineural invasion (PNI) in rectal cancer. Methods and materialsClinical data of 1,232 stage II–III rectal cancer patients from six tertiary institutions were analyzed. All patients were treated by long-course preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Adjuvant systemic chemotherapy was performed for 962 (78.1%) patients according to the multidisciplinary team’s decision. Treatment outcomes and prognostic factors were evaluated according to the lymphovascular invasion (LVI) and perineural invasion (PNI) status. ResultsFive-year overall survival (OS) and recurrence-free survival (RFS) rates of the entire cohort were 84.1% and 71.1%, respectively. There is a significant difference in 5-year OS among both-absent, LVI+ only, PNI+ only, and both-present groups (89.1% vs. 77.9% vs. 67.6% vs. 56.2%; p < 0.001). RFS at five years was significantly different among both-absent, LVI+ only, PNI+ only, and both-present groups (78.7% vs. 58.7% vs. 44.6% vs. 38.6%; p < 0.001). The 5-year distant failure-free survival (DFFS) rate was also significantly different among four groups (84.6% vs. 61.4% vs. 54.2% vs 48.6%; p < 0.001). Although adjuvant chemotherapy did not affect 5-year DFFS in the entire cohort, adjuvant chemotherapy significantly reduced the distant failure rate in patients with PNI+ patients (44.9% vs. 54.6%, p = 0.048), not LVI+ patients (65.0% vs. 56.1%, p = 0.487). ConclusionCompared to LVI, PNI is a more significant prognostic factor in stage II–III rectal patients treated by preoperative CRT and TME surgery. The status of PNI rather than LVI could be an indicator for identifying patients who could benefit from adjuvant systemic chemotherapy.

Construction and validation of a simple scoring system for stage III colorectal cancer recurrence (SiS-SCORE). A case control study.

Stage III colorectal cancer is an indication for adjuvant chemotherapy; however, there is no definite view on the selection of regimen. If the recurrence can be predicted, it can serve as the indicator of regimen selection. The present study aimed to predict the recurrence of stage III colorectal cancer by constructing a simple scoring system. The information of stage III cases that underwent curative surgery was obtained from two facilities and analyzed. A scoring system was constructed from the analysis results and evaluated based on the cases from a different facility. Five factors were extracted by multivariate analysis: age > 65, male, rectum, ≥pN2 and CA19-9 > 37. When these parameters were scored as 1 point each, the score was correlated with the cumulative recurrence rate. Additionally, when cases were divided into three groups (≤1 point, 2 points, ≥3 points), the 5-year recurrence rate was as follows:, ≤1 point: 33.3%, 2 points: 42.1%, ≥3 points: 78.6%. The cumulative recurrence rate of ≥3 points was significantly higher than that of ≤1 point (P < 0.001). Similar results were obtained by evaluating that cases at a different facility (P = 0.032). Both cases with 2 points were located between ≤1 point and ≥3 points, reflecting the average recurrence rate of each institution. As the SiS-SCORE presented the same result in the facility that was different from the base facility, it can be used widely. However, a prospective study is required to prove the usefulness of the SiS-SCORE.

Positive sentinel node in luminal A-like breast cancer patients - implications for adjuvant chemotherapy?

Background: In luminal A-like breast cancer, the indication for adjuvant chemotherapy still is largely based on lymph nodestatus. Sentinel node (SN) positive patients who are no longer recommended an axillary lymph node dissection (ALND) risk undertreatment, especially if they have ≥4 lymph node metastases (LNMs).Aim: To quantify the group of SN positive luminal A-like patients with ≥4 LNMs and to investigate if the ratio between positive SNs and examined SNs (SN ratio) can provide information of the axillary tumor burden.Material and methods: Nearly 370 patients between 2014-2016 in Western Sweden with a clinically node-negative invasive breast cancer treated with both SNB and subsequent ALND were included. SNB findings were compared to ALND findings and the ability of the SN ratio to describe the axillary tumor burden was evaluated using multivariable analysis.Results: In total,17.6% of patients with luminal A-like tumors had ≥4 LNMs. The SN ratio was statistically significant for predicting ≥4 LNMs among luminal A-like patients (p = .013, OR 1.89 (95% CI 1.14–3.12) per 0.1 increment in SN ratio).Conclusions: One sixth of patients with SN positive luminal A-like tumors risk undertreatment. The SN ratio may aid in identifying many of these patients.

Assessment of Ki67 and uPA/PAI-1 expression in intermediate-risk early stage breast cancers

BackgroundThe objective of this study was to compare the efficacy of biomarkers in assessing the risk of breast cancer recurrence in patients with node-negative or micrometastatic grade II breast cancer. Specifically, we compared risk assessments based on the St. Gallen clinicopathological criteria, Ki67 expression and urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) expression.MethodsThis retrospective study included 347 patients with breast cancer followed at Limoges University Hospital. The optimal cut-off for high Ki67 expression (Ki67hi) was established as 20%. The threshold for uPA and PAI-1 positivity was 3 ng/mg and 14 ng/mg, respectively.ResultsKi67 expression was lower in uPA/PAI-1-negative than in uPA/PAI-1-positive tumours (227 tumours; P = 0.04). The addition of Ki67 status to the St. Gallen criteria resulted in a 28% increase in the rate of identification of high-risk tumours with a potential indication for chemotherapy (P < 0.001). When considering uPA/PAI-1 levels together with the St Gallen criteria (including Ki67 expression), the number of cases identified as having a high recurrence risk with a potential indication for adjuvant chemotherapy increased by 20% (P < 0.001). Adjuvant chemotherapy was 9% less likely to be recommended by a multidisciplinary board when using the current criteria compared with using a combination of the St. Gallen criteria and Ki67 and uPA/PAI-1 status (P = 0.03).ConclusionsTaken together, our data show discordance among markers in identifying the risk of recurrence, even though each marker may prove to be independently valid.

Outcomes and prognostic factors of localized, resected malignant salivary gland tumors: Examining a single institution’s 12-year experience to discover indications for adjuvant chemotherapy.

e17587 Background: Survival outcomes remain poor in salivary gland malignancies (SGMs) with multiple poor prognostic factors despite adjuvant radiotherapy. We examined prognostic factors that portended poor survival in resected SGMs to determine possible indications for adjuvant chemoradiotherapy. Methods:Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and retrospective chart review was performed. Bivariate analysis was performed on continuous variables using Analysis of Variance. Chi-Square analysis and Fishers Exact Tests were performed on categorical variables. To evaluate the overall survival (OS) and disease-free survival (DFS), Kaplan-Meier curves and log-rank tests of homogeneity were used. Results: Overall, 99 patients met inclusion criteria. Median follow-up time was 46.8 months. Univariate analysis revealed male sex, smoking history ≥ 10 pack-years, high grade, stage III-IVB, squamous cell histology, and perineural invasion significantly impacted OS and DFS. High-risk histopathology significantly impacted DFS and trended towards poor OS. Positive resection margins trended towards significantly impacting DFS. Multivariate analysis revealed only male sex and perineural invasion significantly impacted OS and DFS. Conclusions: Survival outcomes remain poor for patients with high-grade, late-stage tumors with perineural invasion. Specifically, perineural invasion is a poor prognostic factor regardless of age, histology, stage, and grade. Males and patients with a smoking history ≥ 10 pack-years have worse survival outcomes with male sex being a more influential prognostic factor. Notably, this is the first study to quantify patient’s smoking history in malignant salivary gland tumors and assess the impact of pack-year smoking history on survival outcomes. Given our observed trend, positive resection margins would likely become significant influencer of DFS with larger sample size and longer follow up. Adjuvant chemoradiotherapy should be evaluated in patients with the above-mentioned characteristics.

Abstract P6-09-10: Results of multigene assay (MammaPrint®) and molecular subtyping (BluePrint®) substantially impact treatment decision making in early breast cancer: Final analysis of the WSG PRIME decision impact study

Abstract P6-09-10: Results of multigene assay (MammaPrint®) and molecular subtyping (BluePrint®) substantially impact treatment decision making in early breast cancer: Final analysis of the WSG PRIME decision impact study

Abstract P5-14-06: The effect of adjuvant chemotherapy in a large consecutive series of ER-pos HER-2 negative early breast cancers

Abstract Background: The last EBCTCG-overview reported, in general, a significant better breast cancer outcome if adjuvant chemotherapy was added to surgery and endocrine therapy in ER-pos breast cancers, but the precise indication for adjuvant chemotherapy in this population remains controversial. We study the effect of adjuvant chemotherapy on breast cancer outcome in consecutive patients with an ER-pos HER-2 negative breast cancer treated with adjuvant antihormonal therapy. Methods: Data were collected prospectively from consecutive patients with non-metastatic breast cancer that were primary operated between 2000 and 2012 at the University Hospitals Leuven (Belgium). A Propensity Score (PS) weighted analysis was performed to estimate the average treatment effect (ATE). The primary endpoint was recurrence free interval (RFI). Secondary endpoints were distant recurrence free interval (D-RFI) and breast cancer specific survival (BCSS). Covariates used to generate the propensity score and to include in the PS weighted analysis were age at diagnosis, body mass index, tumor size, grade, pN, lymph vessel invasion, PR, and radiotherapy. Cause-specific hazard models were fitted, using death not from breast cancer as competing risk. Treatment heterogeneity was examined by evaluating interactions of each covariate with adjuvant chemotherapy, using the Bonferroni-Holm method to correct for multiple testing. Results: In the total cohort of 5609 patients, 4282 had a hormone sensitive HER-2 neg breast cancer and 4121 (96.2%) of these received adjuvant antihormonal therapy. Adjuvant chemotherapy was given in 1179/4121 patients (29%). Median follow-up was 8.5 years. Due to very strong differences between patients with and without adjuvant chemotherapy, a restricted PS weighted analysis was used according to a recent recommendation in the statistical literature. This analysis is based on 1750 patients with a PS between 0.1 and 0.9. In this group, 807 (46%) received adjuvant chemotherapy, 211 (12%) observed an event for RFI, 167 (10%) for D-RFI, and 108 (6%) for BCSS. Adjuvant chemotherapy was associated with better prognosis: the adjusted cumulative incidence of recurrence within 5 years was 9.7% without and 5.3% with adjuvant chemotherapy. The adjusted hazard ratio for RFI was 0.50 (95% CI 0.33-0.74). There were no strong interactions with adjuvant chemotherapy. Results for D-RFI and BCSS were similar. Conclusion: Based on PS analysis to reduce confounding and chemotherapy indication bias, we observed clear benefit from adjuvant chemotherapy in ER-pos HER-2 negative breast cancers. Citation Format: Van Calster B, Neven P, Wildiers H, Punie K, Jongen L, Han S, Berteloot P, Van Nieuwenhuysen E, Nevelsteen I, Smeets A, Floris G. The effect of adjuvant chemotherapy in a large consecutive series of ER-pos HER-2 negative early breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-14-06.

Ileostomy Reversal in Rectal Cancer: Outcomes After Neoadjuvant Radiation Therapy

The consequences of anastomotic leakage following colorectal resection are severe. A recent Cochrane review supports the use of a covering stoma to reduce the consequence of distal anastomotic failure, particularly following neoadjuvant radiation therapy. It has been reported in recent publications that as much as 20-25% of temporary stomas are never reversed after radiation therapy due to operative complications. Our present study aims to review our institutional experience of temporary ileostomy reversal after preoperative radiation therapy. Data were collected retrospectively on consecutive patients undergoing definitive total mesorectal excision (TME) for rectal cancer. Patients were treated with preoperative radiation between January 2009 and June 2015. The radiation therapy was either given as standard 3D conformal radiation therapy with 5-FU based chemotherapy (CTRT, 50.4 Gy in 28 fractions) or high dose rate brachytherapy alone (HDRBT, 26 Gy in 4 fractions). Data were collected on reversal of ileostomy rates, time to reversal, reasons for delayed reversal (defined as > 6 months) and complications following reversal. A total of 386 patients were treated with preoperative radiation therapy at our center. These included 244 lower anterior resections (LAR, 63%) and 142 abdominoperineal resections (APR, 37%). Among the patients who were planned for LAR, there were 4 Hartmann procedures and 5 who had immediate anastomosis: these patients were excluded from the present analysis. Furthermore, there are 26 patients who had indications for adjuvant chemotherapy and have not yet been scheduled for reversal. As a consequence, 209 patients were retained for analysis. The median age at time of TME is 64 years; 92 patients were female (44%) and 117 were male (56%). The median time to ileostomy reversal was 7 months (range 1-29). The ileostomy closure rate was 89% (187/209), with no statistically significant difference between patients undergoing CTRT or HDRBT. The causes of ileostomy non-closure were: patient death from non-cancer cause (7/209, 3.3%), patient refusal (1/209, 0.5%), local recurrence (5/209, 2.4%), metastatic disease (4/209, 1.9%) and local complications (5/209, 2.4%). In our experience, the use of preoperative radiation does not have a negative impact on the ileostomy reversal rate, with a contribution to local complication rate of 2.4%. Our results compare favorably to the rate of 20-25% reported in the literature.

Clinical Staging of Stage I Non-Small Cell Lung Cancer in the Netherlands—Need for Improvement in an Era With Expanding Nonsurgical Treatment Options: Data From the Dutch Lung Surgery Audit

The clinical stage of non-small cell lung cancer (NSCLC) determines the initial treatment, whereas the pathologic stage best determines prognosis and the need for adjuvant treatment. In an era in which stereotactic ablative radiotherapy (SABR) has become an alternative modality to surgical intervention, clinical staging is even more important, because pathologic staging is omitted in the case of SABR. The objective of this study was to determine the concordance between clinical and pathologic stage in routine clinical practice for patients with early-stage NSCLC. Prospective data were derived from the Dutch Lung Surgery Audit (DLSA) in 2013 and 2014. Patients with clinical stage I NSCLC who underwent surgical resection and had a positron emission tomography-computed tomography (PET-CT) scan in their clinical workup were selected. Clinical and pathologic TNM (cTNM and pTNM) stages were compared. From a total of 1,790 patients with clinical stage I, 1,555 (87%) patients were included in this analysis. Concordance between cTNM and pTNM was 59.9%. Of the patients with clinical stage I, 22.6% were upstaged to pathologic stage II or higher. In total, 14.9% of all patients with clinical stage I had nodal metastases, and5.5% of all patients had unforeseen N2 disease. In patients with clinical stage T2a tumors, 21.3% had nodal metastases, 14.5% being N1 and 6.7% being N2 disease. Concordance between clinical and pathologic stage is 59.9%. In patients with clinical stage I NSCLC, 22.6% were upstaged to pathologic stage II or higher, which is an indication for adjuvant chemotherapy. Improvement in accuracy of staging is thus needed, particularly for these patients.

Interlaboratory Variability in the Histologic Grading of Colorectal Adenocarcinomas in a Nationwide Cohort.

Differentiation grade of colorectal adenocarcinoma (CRC) is a prognostic factor and important for therapy selection. In patients with stage II colon cancer, poor differentiation is an indication for adjuvant chemotherapy. The variability in daily practice in the grading of CRC was assessed in a nationwide cohort. Using the Dutch Pathology Registry (PALGA), all synoptically reported CRC resections from 2010 to 2013 were identified. Proportions of poorly differentiated (PD) adenocarcinomas were determined and compared between 35 laboratories by univariable and multivariable logistic regression analyses. In total, 11,719 resections of 11,681 patients were included, of which 1427 (12.2%) were PD (range between 35 laboratories: 5.0% to 33.2%). After adjustment for case mix, 4 (11%) laboratories still reported a significantly lower (n=2) or higher (n=2) proportion of PD adenocarcinoma compared with the reference laboratory. Seven of 8 investigated laboratories showed considerable intralaboratory variation between pathologists as well. In a subgroup of 2812 patients (2813 tumors) who could have been eligible for adjuvant chemotherapy solely on the basis of the differentiation grade (stage II colon cancer patients without other high-risk factors [ie, T4, <10 lymph nodes evaluated, perforation, ileus, or angioinvasion]), 258 (9.2%) were PD (range between laboratories: 0% to 22.7%). In this subgroup, 4 laboratories still diagnosed significantly more PD adenocarcinomas after multivariable logistic regression analysis, increasing the number of colon cancer patients eligible for adjuvant therapy. In conclusion, this large nationwide cohort demonstrates considerable interlaboratory and intralaboratory variation in differentiation grading of CRC. Better standardization of grading criteria is needed for optimal determination of prognosis and treatment selection.

Abstract P1-01-03: Variability of Ki67 labeling index depending on different measurements in luminal type breast cancers

Abstract Background: Hormone receptor-positive and HER2-negative breast cancers are divided into luminal A (LA) and luminal B (LB) types using a cutoff of 14% Ki67 labeling index (LI). LB type breast cancer is associated with poor prognosis compared with LA, and considered as an indication of adjuvant chemotherapy. The main obstacles in classification of luminal type breast cancers are non-standardized measurement and Ki67 heterogeneity. We aimed to assess Ki67 variability depending on different methods of measurement and spot selection, and to assess Ki67 heterogeneity in luminal type breast cancers. Design: We retrospectively retrieved 174 Ki67 stained slides of surgically excised invasive breast cancers with ER+ and/ or PR+, HER2-, and Ki67 LI of 10-20% range. On each slide, 3 spots of low, intermediate, and high Ki67 labeling densities were captured via camera snapshot. And then, Ki67 LI was measured by digital image analysis (DIA) and manual count (MC) on 3 captured spots. Each case was classified into LA and LB types based on Ki67 LI measured by 4 methods; hot spot index by DIA; average index by DIA; hot spot index by MC; average index by MC. Ki67 heterogeneity was defined by the tumor with Ki67 KI &amp;lt;5% in low labeled spot, and ≥14% in high labeled spot by DIA. Correlation between the Ki67 heterogeneity and pathological parameters were analyzed. Result: Ki67 LI measured by DIA was higher than by MC in 3 spots (low: 4.95 vs. 3.39, p&amp;lt;0.001; intermediate: 10.07 vs.9.26, p=0.058; high: 14.88 vs. 14.03, p=0.025) with the biggest difference in low labeled spot. The 4 methods showed poor agreement on classification of LA/LB types. The proportion of LB type ranged from 3.4% to 60.9% depending on methods. Classification of luminal A and luminal B types by different methods Luminal ALuminal BHot spot index-DIA68 (39.1%)106 (60.9%)Average index-DIA157 (90.2%)17 (9.8%)Hot spot index-MC82 (47.1%)92 (52.9%)Average index-MC168 (96.6%)6 (3.4%) Forty two of 174 cases (24.1%) showed Ki67 heterogeneity. Ki67 heterogeneity was most frequent in T2 (p=0.001) and histologic grade 3 (p=0.023) tumors. Comparison of pathological features according to Ki67 heterogeneityKi67 heterogeneityAbsentPresentp-valueNumber 132(75.9%)42 (24.1%) T stageT195(84.1%)18(15.9%)0.001 T232(58.2%)23(41.8%) T35(83.3%)1(16.7%) Histologic grade130(90.9%)3(9.1%)0.023 293(74.4%)32(25.6%) 39(56.2%)7(43.8%) SubtypeInvasive ductal carcinoma, NOS114(74%)40(26%)0.475 Invasive lobular carcinoma8(88.9%)1(11.1%) Mucinous carcinoma4(80%)1(20%) Others (invasive micropapillary, tubular, etc.)6(100%)0(0%) Conclusion: Ki67 LI is markedly variable depending on different measurements and spot selections. Ki67 heterogeneity exists in 24.1% of luminal breast cancers in this series. Therefore, whole section slides should be preferred for Ki67 LI measurement, rather than tissue microarray or biopsy specimen which may not entirely reflect the proliferation index of the tumor. Citation Format: Kim S, Moon B-I, Sung SH. Variability of Ki67 labeling index depending on different measurements in luminal type breast cancers. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-01-03.

Value of a gene signature assay in patients with early breast cancer and intermediate risk: a single institution retrospective study

Purpose In daily clinical practice, the indication for adjuvant chemotherapy (CT) is relatively easy to make in patients with early hormone-receptor-positive (HR+) breast cancer with either very poor or very good clinicopathological prognostic variables. However, this decision is much more difficult in patients with intermediate clinicopathological prognostic variables. Here, we evaluate the value of a gene-expression profile identified by the Prosigna gene signature assay in guiding treatment decision-making in patients with these intermediate features.Methods A consecutive cohort of 577 HR + breast cancer patients surgically treated in a single institution between January 2012 and December 2012 was evaluated. From this population, pre- and post-menopausal patients with intermediate prognosis clinicopathological variables were identified and indication of adjuvant CT in these patients was recorded. The gene signature assay was performed retrospectively in this intermediate risk group. Descriptive statistics are presented.Results Among 96 intermediate-risk patients, 64 postmenopausal patients underwent gene signature testing. Subtype distribution was as follows: Luminal A (N = 33; 51.6%), Luminal B (N = 31; 48.4%). Risk of recurrence (ROR) distribution was as follows: ROR-low (n = 16; 25%); ROR-intermediate (N = 26; 40.6%); and ROR-high (N = 22; 34.4%). CT was subsequently administered in 18.7%, 53.8% and 59.0% of the ROR-low, ROR-intermediate and ROR-high groups, respectively. With the use of the gene signature assay, 59.4% of the intermediate cases were re-classified to either ROR-low or ROR-high risk categories. In the ROR-intermediate group, 11/26 patients (42.3%) had Luminal A and 15/26 (57.7%) had Luminal B. Due to follow-up time constraints, no patient outcome results were evaluated.Conclusion The gene signature assay provides clinically useful information and improved treatment decision-making in patients with intermediate risk based on clinicopathological factors. Determining the patient’s intrinsic subtype and ROR can aid clinicians in deciding whether CT should be indicated.

Prognostic risk factors for treatment decision in pT1a,b N0M0 HER2-positive breast cancers.

Although outcomes for women with breast cancers may vary by biologic subtype, patients with T1a,b N0M0 tumors have an excellent prognosis across all subgroups. HER2 overexpression occurs in 15-20% of primary breast tumors, and is associated with diminished disease-free and overall survival. The anti-HER2 monoclonal antibody trastuzumab in combination with chemotherapy is an effective treatment for all stages of HER2 positive breast cancer (bc). However, the absolute benefit decreases as the risk of recurrence lessens and no available randomized adjuvant trial has evaluated the role of trastuzumab in women with pT1a,b N0M0, HER2-positive breast tumors. These findings may explain the debate about the appropriate indication for adjuvant chemotherapy plus trastuzumab in this setting of patients. The aim of this review was to describe known and novel prognostic risk factors to be used for tailored treatment decision in pT1a,b N0M0 HER2-positive tumors. Whether patients with small HER2-positive bc may be suitable for (chemo)therapy reduction strategies, the current available data cannot exclude the need for a more aggressive treatment in a small subset of these subjects. Novel clinical prognostic factors such as interval cancer (IC) detection may help to address this clinically important controversy. A multicenter population-based cancer registry study is currently evaluating whether IC detection may identify patients with pT1a N0M0 HER2-positive tumors in whom the rate of recurrence justifies consideration for use of conventional, trastuzumab-based chemotherapy regimens.