Node-negative Tumors Research Articles

Patterns of care and outcomes among triple-negative early breast cancer patients in South Western Sydney.

Triple-negative breast cancer (TNBC) represents 12-24% of all breast cancer and carries a poor prognosis upon recurrence. Little is known of the treatment, or timing and frequency of recurrences outside of a clinical trial. We describe the patterns of care and outcomes of women with TNBC treated at two cancer centres in Sydney, NSW, Australia, to help oncologists talk to women with this subtype of breast cancer about their likely prognosis. We searched the electronic medical record for women with stages I-III TNBC diagnosed from 2006 to 2014. For each woman, we recorded demographics, tumour characteristics, treatment details, recurrences and survival using the Kaplan-Meier method. We identified 137 women with a median age of 55 years (interquartile range (IQR) 44-63). The median tumour size was 25 mm (IQR 16-35). Most women had grade 3 (92%) and ductal carcinomas (89%), and 35% were node positive; 113 (82%) patients received (neo)adjuvant chemotherapy. The most prescribed regimens for node-negative tumours were: fluorouracil, epirubicin and cyclophosphamide (FEC) × 6 (23pts, 35%), and for node-positive tumours, FEC-Docetaxel (18pts, 40%). Adjuvant radiotherapy was delivered to 114 (83%) patients. After a median follow up of 40 months, 17 patients (12%) had a recurrence. All but one recurrence (94%) occurred within 3 years of diagnosis. Twelve women received palliative chemotherapy, and 14 women have died. The median survival from the time of recurrence was 18 months (IQR 5-26). Seven women (5%) had a documented BRCA1 mutation, and four women (3%) had a documented BRCA2 mutation. TNBC affects women at a relatively young age and tends to recur early. Survival following metastatic disease is short, and more effective therapies are needed.

Galectin-9 Expression Predicts Favorable Clinical Outcome in Solid Tumors: A Systematic Review and Meta-Analysis

Background and Objective: Galectin-9 (Gal-9) is one of the galectin family members which are known as proteins with β-galactoside-binding affinity. Accumulative evidence suggest that Gal-9 plays multifaceted roles in tumor biology. However, the prognostic significance of Gal-9 in solid cancer patients remains controversial. The objective of the study was to clarify the prognostic significance of Gal-9 in solid tumors via meta-analysis.Methods: We searched PubMed, Embase and the Cochrane library for studies that report the correlation between Gal-9 expression and prognosis or clinicopathological parameters in solid cancer patients from inception to October 2017, with no language restriction. We calculated pooled hazard ratio (HR) and 95% confidence interval (CI) to investigate the prognostic significance of Gal-9 expression in solid tumors. We also calculated Odds ratio (OR) to explore the association between Gal-9 expression and clinicopathological features.Results: We included Fourteen studies with 2326 patients in our meta-analysis. The synthetic results revealed that high Gal-9 expression indicated improved overall survival (OS; HR = 0.70, 95% CI = 0.51–0.71, P = 0.006) but had no correlation with disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.85, 95% CI = 0.51–1.41, P = 0.527) in solid tumors. In stratified analyses, high Gal-9 expression was significantly correlated with improved OS in hepatocellular carcinoma and colon cancer and with improved DFS/RFS in gastric cancer and non-small cell lung cancer. In addition, ethnicity and the method of data extraction didn’t affect the positive prognostic values of high Gal-9 expression. Moreover, high Gal-9 expression was significantly correlated with a smaller depth of invasion (TI/TII vs. TIII/TIV, OR = 2.80, 95% CI = 1.97–3.96, P < 0.001), an earlier histopathological stage (I/II vs. III/IV, OR = 3.00, 95% CI = 2.04–4.42, P < 0.001), negative lymph node metastasis (Presence vs. Absence, OR = 0.47, 95% CI = 0.25–0.89, P = 0.020) and negative distal tumor metastasis (Presence vs. Absence, OR = 13.85, 95% CI = 3.50–54.76, P < 0.001).Conclusion: Gal-9 expression indicates beneficial outcome in patients with solid tumors and is correlated with the pathogenesis of solid tumors. Gal-9 may serve as a prognostic biomarker and an emerging therapeutic target against solid tumors.

RNA Oncoimmune Phenotyping of HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas by Nodal Status

Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16-positive/p16-positive OPSCCs. This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16-positive tumors were used in this study. Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative-like from node-positive-like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population's prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Many HPV-16 and p16-positive tumors are treated as "lower-risk," but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.

Intrahepatic cholangiocarcinoma : Results after 84 resections

The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing worldwide. Surgical resection is the only curative treatment option. This study analyzed the prognostic factors after resection of ICC. A total of 84patients were surgically treated under potentially curative intent. Perihilar and distal cholangiocarcinomas were excluded. The 5‑year survival was analyzed with respect to tumor stage (TNM), number of lesions, complete surgical resection (R0), peritoneal carcinosis and postoperative complications. The 5‑year survival was 27% and 77% of patients underwent R0 resections. In the univariate analysis a Tstage >2, an N+ situation or an R+ resection as well as peritoneal and multilocular intrahepatic spread were associated with apoorer prognosis. Postoperative complications also negatively influenced survival. On multivariate analysis the absence of peritoneal spread, node-negative tumor stages, singular hepatic lesions and alow Tstage as well as the absence of complications were associated with improved survival. The prognosis of ICC is poor even after successful surgical resection. Well-known tumor characteristics such as TNM are relevant prognostic factors. Surgical resection is accompanied by postoperative complications (most frequently biliary), which negatively influence survival. Adjuvant strategies are urgently needed to improve long-term survival even after complete surgical resection.

Abstract P1-07-05: AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma

Abstract Background: Estrogen receptor (ER) positive HER2-negative breast cancer comprises 75–80% of all breast cancer. This fraction is even higher (&amp;gt;90%) in invasive lobular carcinoma (ILC). According to the St Gallen surrogate definitions of the intrinsic subtypes, Ki67 and progesterone receptor (PgR) are used to classify these tumors as luminal A- and luminal B-like (HER2-negative). These guidelines are based on information derived from patient materials with mixed histological types, where the vast majority of the patients have invasive ductal carcinoma. The `luminal-like classification´ together with histological grade, tumor size and lymph node status is widely used in the clinic for prognostication. The aim of the present study was to investigate if the same markers are applicable for ILC, and furthermore, if additional biomarkers involved in the endocrine signaling system, e.g. Amplified in breast cancer 1 (AIB1) and the putative G protein-coupled estrogen receptor (GPER), might provide complementary prognostic information. Patients: Two hundred and thirty-three (N = 233) well-characterized patients with primary ILC, diagnosed between 1980 and 1991 were included. Forty-two percent of the patients received adjuvant endocrine treatment and 2 % received adjuvant chemotherapy. All biomarkers were analyzed immunohistochemically on tissue microarray, whereas histological grade was evaluated on whole sections according to Elston and Ellis (NHG). The primary endpoint was breast cancer mortality (BCM). Results: In univariable analyses with 10-year follow-up, Ki67 (high vs. low), NHG (3 vs. 1+2) and AIB1 (high vs. low) were significantly associated to BCM (Hazard Ratio: 4.7, 95% CI: 2.1–10.4, p &amp;lt;0.001; HR: 3.1, 95% CI: 1.5–6.4, p = 0.003; HR: 3.2, 95% CI: 1.4–7.2, p = 0.005 respectively), whereas PgR (&amp;lt;1% vs ≥1%) and GPER (linear 0-4) were not (p = 0.25; p = 0.31 respectively). Essentially the same effect was seen after multivariable adjustment for lymph node status (+ vs. -), tumor size (&amp;gt;20 mm vs. &amp;lt;20 mm), adjuvant treatment and age (continuous). Subgrouping the tumors into luminal A- and B-like (HER2-negative) according to St Gallen surrogate definitions did not show significant prognostic differences between the two groups (p = 0.12). Patients with &amp;lt;20 mm, lymph node negative breast cancer and favorable tumor characteristics (low Ki67, NHG 1+2, and low AIB1) had a 10-year BCM of 4.2% (95% CI: 1.4–12%). This group constituted 34% of the patients included in the present study. Conclusions: In contrast to other previous studies, where breast cancers of mixed histological types were included, PgR was not significantly associated to prognosis in the ER-positive HER2-negative subgroup in the present study, consisting only of ILC. The prognostic role of PgR and the clinical usefulness of the luminal A and B-like (HER2-negative) classification (using only Ki67 and PgR) in ILC is still to be further investigated. The prognostic importance of Ki67 and NHG in this subgroup was, however, confirmed also in ILC, and AIB1 might be a new putative prognostic factor. By combining Ki67, NHG, and AIB1, together with lymph node status and tumor size, a group of patients with an excellent prognosis could be identified. Citation Format: Narbe U, Forsare C, Bendahl P-O, Lövgren K, Alkner S, Sjöström M, Rydén L, Leeb-Lundberg F, Ingvar C, Fernö M. AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma [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 P1-07-05.

Abstract CS1-1: Adjuvant endocrine therapy for premenopausal ER+ breast cancer

Abstract Adjuvant therapy decisions for premenopausal ER+ve breast cancer are challenging. An analysis from TEXT found that therapy varied by geography.1 Approximately half the women with node negative tumors enrolled from North America received optional adjuvant chemotherapy, in addition to protocol ovarian suppression plus oral endocrine therapy, while only one quarter of women with node negative tumors enrolled from Italy received chemotherapy. For women with node positive tumors, the use of chemotherapy was almost universal (93%) in North America, while 27% enrolled from Italy did not receive chemotherapy. Use of multigene assays may reduce future use of chemotherapy in ER+ve breast cancer, however limited information exists for outcomes of young women with low risk assay results, treated with tamoxifen alone. Among 6,693 women enrolled in MINDACT, only 44 women were under age 35 with low genomic risk.2 Only 58 women aged 40 or under were included in the Tailor-X Recurrence Score 0-10 cohort and not all received tamoxifen alone.3 Chemotherapy may provide an indirect endocrine effect in premenopausal ER+ve breast cancer, due to suppression of ovarian estrogen production. The EBCTCG meta-analysis published in 1998 reported that 5 years of adjuvant tamoxifen was effective, regardless of age, menopausal status or chemotherapy.4 Adjuvant ovarian ablation is effective for women under 50 as a sole adjuvant therapy,5 but the value of ovarian suppression/ablation in premenopausal women with ER+ve tumors who also receive tamoxifen, with or without adjuvant chemotherapy, has been uncertain.6 SOFT randomized premenopausal women with hormone receptor-positive breast cancer to receive 5 years of tamoxifen or tamoxifen plus ovarian suppression or exemestane plus ovarian suppression.7 The initial results, after median 5.6 years follow-up, did not show a significant benefit from addition of ovarian suppression to tamoxifen in the overall premenopausal population. SOFT was stratified by use of prior chemotherapy and in the cohort who did not receive chemotherapy, women allocated tamoxifen alone had few recurrences and virtually no distant recurrences during the first 5 years. However, for patients in SOFT deemed at sufficient risk to receive chemotherapy and who remained premenopausal, the addition of ovarian suppression to tamoxifen did reduce risk of invasive recurrence during the first 5 years, and the use of exemestane with ovarian suppression further reduced recurrence. The joint analysis of TEXT and SOFT found that exemestane plus ovarian suppression significantly improved DFS compared with tamoxifen plus ovarian suppression.8 The absolute benefit of endocrine therapies that included ovarian suppression in SOFT and TEXT, as compared with tamoxifen alone, was most striking in women under age 35, although women with a high risk of recurrence from a combination of clinical-pathologic factors (composite risk) could also derive benefit.9

Differential Expression of TFF Genes and Proteins in Breast Tumors.

SUMMARY – The objective of this study was to determine differential expression of TFF1, TFF2 and TFF3 genes and proteins in breast tumor subtypes. In addition, we investigated the correlation between TFF genes within tumor subgroups, and TFF genes with clinical and pathologic characteristics of the tumor. Study group included 122 patients with surgically removed breast tumors. Samples were investigated using qRT-PCR and immunohistochemistry. TFF1 and TFF3 genes and proteins were expressed in breast tumors, while the levels of TFF2 gene and protein expression were very low or undetectable. TFF1 was significantly more expressed in benign tumors, while TFF3 was more expressed in malignant tumors. Gene and protein expression of both TFF1 and TFF3 was greater in lymph node-negative tumors, hormone positive tumors, tumors with moderate levels of Ki67 expression, and in grade II tumors. A strong positive correlation was found between TFF1 and TFF3 genes, and the expression of both negatively correlated with Ki67 and the level of tumor histologic differentiation. Our results suggest that TFF1 and TFF3, but not TFF2, may have a role in breast tumor pathogenesis and could be used in the assessment of tumor differentiation and malignancy.

Adherence to Adjuvant Endocrine Therapy in Christchurch Women with Early Breast Cancer

AimsTo assess adherence to adjuvant endocrine therapy by a real-world cohort of women in Christchurch and to determine any associated factors. Materials and methodsRecords were retrieved of all women newly diagnosed with early breast cancer and registered on the Christchurch Breast Cancer Patient Register over 4 years from June 2009. Demographic and pathological factors, dates of starting and stopping endocrine therapies and reported side-effects were collected. The proportion remaining on endocrine therapy was analysed by Kaplan–Meier curve; Cox regression analysis was used to identify independent factors influencing adherence. ResultsOf 1213 women, 1018 (83.9%) had oestrogen receptor-positive tumours, of whom 674 (66.2%) started adjuvant endocrine therapy, including 62 (9.2%) neoadjuvantly. Uptake was 52.4% of those with T1 tumours, 89% with T2 tumours, 93% with T3/T4 tumours, 92.7% with node-positive tumours and 49.7% with node-negative tumours. The initial endocrine therapy was an aromatase inhibitor in 254 (38%) and tamoxifen for 412 (61%). At 1 year, 90% remained adherent, at 2 years 84%, at 3 years 81%, at 4 years 76%, at 4.5 years 71% and at 5 years 50%, with a median duration of 60 months (56–64 months, 95% confidence interval) and a median follow-up of 33 months. Overall, 135 (20%) women stopped treatment for adverse events or poor tolerability. A longer persistence with endocrine therapy was associated with node-positive tumours (hazard ratio 1.38, P = 0.003), but not first hormone used; aromatase inhibitor compared with tamoxifen, P = 0.76. ConclusionAdjuvant endocrine therapy use fell to 50% by 5 years, limiting possible survival benefits, providing support for efforts to increase compliance.

Prospective, multicenter French study evaluating the clinical impact of the Breast Cancer Intrinsic Subtype-Prosigna® Test in the management of early-stage breast cancers.

PurposeThe Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna’s assay information on physicians’ adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results.MethodsConsecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians’ opinion on the test results and the patients’ degree of anxiety, difficulties with therapy and quality of life.ResultsBetween March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher’s exact test). Prosigna test results also decreased patients’ anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty.ConclusionsThe results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

MicroRNA-200, associated with metastatic breast cancer, promotes traits of mammary luminal progenitor cells.

MicroRNAs are critical regulators of gene networks in normal and abnormal biological processes. Focusing on invasive ductal breast cancer (IDC), we have found dysregulated expression in tumor samples of several microRNAs, including the miR-200 family, along progression from primary tumors to distant metastases, further reflected in higher blood levels of miR-200b and miR-7 in IDC patients with regional or distant metastases relative to patients with primary node-negative tumors. Forced expression of miR-200s in MCF10CA1h mammary cells induced an enhanced epithelial program, aldehyde dehydrogenase (ALDH) activity, mammosphere growth and ability to form branched tubuloalveolar structures while promoting orthotopic tumor growth and lung colonization in vivo. MiR-200s also induced the constitutive activation of the PI3K-Akt signaling through downregulation of PTEN, and the enhanced mammosphere growth and ALDH activity induced in MCF10CA1h cells by miR-200s required the activation of this signaling pathway. Interestingly, the morphology of tumors formed in vivo by cells expressing miR-200s was reminiscent of metaplastic breast cancer (MBC). Indeed, the epithelial components of MBC samples expressed significantly higher levels of miR-200s than their mesenchymal components and displayed a marker profile compatible with luminal progenitor cells. We propose that microRNAs of the miR-200 family promote traits of highly proliferative breast luminal progenitor cells, thereby exacerbating the growth and metastatic properties of transformed mammary epithelial cells.

A Systematic Analysis of Oncogenic Gene Fusions in Primary Colon Cancer.

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X-ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node-negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy. Cancer Res; 77(14); 3814-22. ©2017 AACR.

Abstract 490: Identification of oncogenic gene fusions in primary colon cancers

Abstract Introduction: Fusion genes (such as ALK-EML) are potentially attractive targets for anti-cancer treatment. In the era of personalized medicine exploring the identification, incidence, and functionality of fusion genes may contribute to effective treatment approaches. Methods: We performed a comprehensive and unbiased screening for gene fusions in a clinically well-defined prospectively collected cohort of 278 primary stage I to III colon cancers. Illumina RNA sequencing was performed using RNA from the fresh frozen samples. The STAR fusion gene detection pipeline and GATK RNA-seq variant calling were used to identify fusion genes and detect somatic genetic variations. Gene fusions were considered relevant when recurrent, when resulting in divergent expression (outlier analysis) or when functional relevance was predicted (i.e. kinase fusions). Results: 2.5% of all samples contained a relevant gene fusion. Kinase fusions were most prevalent with a frequency of 1.8%. Three BRAF-fusions were identified, two known (TRIM24-BRAF &amp; AGAP3-BRAF) and one novel fusion (DLG1-BRAF). Co-expression with ERK1 in HEK293 cells resulted in enhanced EKR1 phosphorylation. The outlier analysis revealed four unique fusions (EML4-NTRK3, RRBP1-RET, USPX9-ERAS &amp; EIF3E-RSPO2). The EML4-NTRK3 fusion led to increased expression of the tyrosine kinase encoding domain exons, which is retained in the fusion transcript. Co-expression with ERK1 in HEK293 cells resulted in enhanced EKR1 phosphorylation. The tumor with the RRBP1-RET fusion was pan negative for known driver mutations, as reported in literature. Mate-pair sequencing of the USPX9-ERAS fusion gene region revealed that the fusion gene was caused at the genomic level by a highly local chromothripsis event on chromosome X spanning solely the region covered by USP9X and ERAS, leading to high ERAS expression. ERAS is a constitutionally active RAS protein and normally only expressed in embryonic stem cells. Analysis of phosphorylated AKT after expression of the USP9X-ERAS fusion gene in NIH-3T3 A14 cells showed activation of AKT signaling. The occurrence of one R-spondin fusion in our set (0.4%) is low compared to the previously described 9.5%, which may be explained by difference in incidence of KRAS- or BRAF-mutations in the two cohorts, since all R-spondin fusions occurred in a tumor with a KRAS- or BRAF-mutation. All fusion genes were expressed in cell lines resulting in the activation of AKT signaling. Finally, oncogenic fusions were only found in lymph node negative tumors and were not observed in tumors with classical driver mutations in BRAF and KRAS except for the R-spondin fusion. Conclusions: We found oncogenic gene fusions including novel fusions with a frequency of 2.5%, including an USP9X-ERAS fusion with strong oncogenic activity in vitro. Although recurrent fusion genes are rare events in colorectal cancer they may represent functional drivers and provide potential novel leads for personalized therapeutic strategies. Citation Format: Robert R. Coebergh van den Braak, Wigard P. Kloosterman, Mark Pieterse, Markus van Roosmalen, Anieta M. Sieuwerts, Christina Stangl, Ronne Brunekreef, Zarina S. Lalmahomed, Salo Ooft, Anne van Galen, Marcel Smid, Armel Lefebvre, Fried J. Zwartkruis, John W. Martens, John A. Foekens, Katharina Biermann, Marco J. Koudijs, Jan N. IJzermans, Emile E. Voest. Identification of oncogenic gene fusions in primary colon cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 490. doi:10.1158/1538-7445.AM2017-490

Neoadjuvant treatment of locally advanced esophageal and junctional cancer: the evidence-base, current key questions and clinical trials

Recent trials, including CROSS, MAGIC, ACCORD, and OEO2, have established neoadjuvant therapy as standard of care for locally advanced (cT2-3NanyM0) esophageal and junctional cancer compared with surgery alone. The CROSS trial in particular defines a new benchmark for outcomes from multimodal therapy, with a 5 year survival rate of 47%, a median survival of 47 months, a pathologic complete response rate (pCR) of 29% and an R0 resection rate of 92%. Several key questions remain, in particular whether CROSS-regimen chemoradiotherapy is superior to neoadjuvant chemotherapy alone for esophageal cancer, in particular adenocarcinoma. Second, with respect to neoadjuvant chemoradiation, whether an apparent complete clinical response can justify a "watch and wait" surveillance policy, with salvage surgery reserved for where relapse occurs. Third, whether with modern staging, predicted node negative cT2 tumors merit neoadjuvant therapy as standard. Finally, with the enormous interest in the application of targeted and immune-based therapies, and positive leads from other cancers, whether such approaches can improve outcomes in patients undergoing treatment with curative intent. We review herein a brief overview of the existing evidence-base and current active trials addressing these key questions.

Selection of optimal molecular targets for tumor-specific imaging in pancreatic ductal adenocarcinoma.

Discrimination of pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) or peritumoral inflammation is challenging, both at preoperative imaging and during surgery, but it is crucial for proper therapy selection. Tumor-specific molecular imaging aims to enhance this discrimination and to help select and stratify patients for resection. We evaluated various biomarkers for the specific identification of PDAC and associated lymph node metastases. Using immunohistochemistry (IHC), expression levels and patterns were investigated of integrin αvβ6, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), Cathepsin E (Cath E), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-MET), thymocyte differentiation antigen 1 (Thy1), and urokinase-type plasminogen activator receptor (uPAR). In a first cohort, multiple types of pancreatic tissue were evaluated (n=62); normal pancreatic tissue (n=8), CP (n=7), PDAC (n=9), tumor associated lymph nodes (n=32), and PDAC after neoadjuvant radiochemotherapy (n=6). In a second cohort, tissues were investigated (n=55) with IHC and immunofluorescence (IF) for concordance of biomarker expression in all tissue types, obtained from an individual patient. Integrin αvβ6 and CEACAM5 showed significantly higher expression levels in PDAC versus normal pancreatic tissue (P=0.001 and P<0.001, respectively) and CP (P=0.003 and P<0.001, respectively). Avβ6 and CEACAM5 expression identified tumor-positive lymph nodes correctly in 84% and 68%, respectively, and in 100% of tumor-negative nodes for both biomarkers. In conclusion, αvβ6 and CEACAM5 are excellent biomarkers to differentiate PDAC from surrounding tissue and to identify lymph node metastases. Individually or combined, these biomarkers are promising targets for tumor-specific molecular imaging of PDAC.

Sterilization of tumor-positive lymph nodes of esophageal cancer by neo-adjuvant treatment is associated with worse survival compared to tumor-negative lymph nodes treated with surgery first.

Lymph node (LN) involvement by esophageal cancer is associated with compromised long-term prognosis. This study assessed whether LN downstaging by neoadjuvant treatment (NAT) might offer a survival benefit compared to patients with a priori negative LN. Patients undergoing esophagectomy for cancer between 2005 and 2014 were screened for inclusion. Group 1 included cN0 patients confirmed as pN0 who were treated with surgery first, whereas group 2 included patients initially cN+ and down-staged to ypN0 after NAT. Survival analysis was performed with the Kaplan-Meier and Cox regression methods. Fifty-seven patients were included in our study, 24 in group 1 and 33 in group 2. Group 2 patients had more locally advanced lesions compared to a priori negative patients, and despite complete LN sterilization by NAT they still had worse long-term survival. Overall 3-year survival was 86.8% for a priori LN negative versus 63.3% for downstaged patients (P = 0.013), while disease-free survival was 79.6% and 57.9%, respectively (P = 0.021). Tumor recurrence was also earlier and more disseminated for the down-staged group. Downstaged LN, despite the systemic effect of NAT, still inherit an increased risk for early tumor recurrence and worse long-term survival compared to a priori negative LN.

Beyond the guidelines: Clinical investigators' (CI) self-reported use of genomic assays (GA) to assist in decision-making regarding use of neoadjuvant (NA) and adjuvant chemotherapy for patients (pts) with ER-positive/HER2-negative (ER+/HER2-) early breast cancer (BC).

e18187 Background: GA, specifically the 21-gene Recurrence Score (RS), have been widely used to help inform decisions regarding use of adjuvant chemotherapy in ER+/HER2- node-negative BC. Although substantial anecdotal evidence exists that clinicians, particularly BC-focused CI, are employing these tests in other situations (node-positive disease, the NA setting), ASCO guidelines do not endorse these practices. Here we aimed to quantify self-reported CI use of GA across a spectrum of hypothetical BC presentations. Methods: In December 2016, a 225-item survey was sent to 97 US-based surgical (S) and medical oncology (MO) CI from a proprietary database. A modest honorarium was provided. Results: 51 CI (26 S and 25 MO) completed the survey. CI generally recommend GA for node-negative tumors but less so for older pts with smaller lesions. 75% of CI reported that they would recommend GA for pts with 1 involved node and 55% would do so for those with 2 to 3 nodes. 31% of CI use GA to guide NA chemotherapy decisions, and 53% who do not use GA in NA decision-making altered their treatment approach when a GA result was available. Conclusions: CI prefer GA when the benefit of chemotherapy is uncertain based on tumor stage and pt age. CI are comfortable using GA in node-negative and node-positive hypothetical cases, and some do so to aid in decisions regarding NA therapy. Quantitative assessment of self-reported CI practice patterns can serve as a complement to established guidelines and provide physicians, pts and third-party payers additional viewpoints on possible appropriate management strategies. [Table: see text]

Perioperative Hepatic Arterial Infusion Pump Chemotherapy Is Associated With Longer Survival After Resection of Colorectal Liver Metastases: A Propensity Score Analysis.

Purpose To investigate whether perioperative hepatic arterial infusion pump chemotherapy (HAI) was associated with overall survival (OS) in patients who had a complete resection of colorectal liver metastases (CLM). Methods Patients who underwent a complete resection of CLM between 1992 and 2012 were included from a single-center prospectively maintained database. All patients who received HAI also received perioperative systemic chemotherapy. Propensity score analysis was used to match patients for seven known prognostic factors. Results A total of 2,368 consecutive patients underwent a complete resection of CLM, with a median follow-up of 55 months. The median OS for patients with HAI (n = 785) was 67 months versus 44 months without HAI (n = 1,583; P < .001), despite more advanced disease in the HAI group. OS at 10 years was 38.0% versus 23.8% without HAI. For patients who received modern systemic chemotherapy (n = 1,442), the median OS was 67 months with HAI and 47 months without HAI ( P < .001). The hazard ratio adjusted by propensity score demonstrated longer OS with HAI: 0.67 (95% CI, 0.59 to 0.76; P < .001). A pronounced difference in median OS was found for patients with node-negative colorectal cancer (129 months with HAI v 51 months without; P < .001) and a low clinical risk score of 0 to 2 points (89 months with HAI v 53 months without; P < .001). Conclusion Patients who received HAI had a median OS of approximately 2 years longer than patients without HAI. The strong association was independent of the use of modern systemic chemotherapy and remained in propensity score analysis. Patients with node-negative primary tumors or a low clinical risk score seemed to benefit most from HAI.

Impact of adjuvant chemotherapy on survival of women with T1N0M0, hormone receptor negative breast cancer

BackgroundThe benefit of adjuvant chemotherapy in women with T1N0M0 breast cancers is unclear. While gene expression-based prognostic assays may aid management of women with early estrogen receptor (ER) positive tumors, therapeutic decision-making in women with early stage ER negative tumors remains fraught with difficulties. We investigated the association between adjuvant chemotherapy and overall survival in women with T1N0M0, hormone receptor negative breast cancers. MethodAll newly diagnosed breast cancer patients with node-negative and hormone receptor negative tumors measuring≤2cm at the University Malaya Medical Centre (Malaysia) from 1993 to 2013 were included. Mortality of patients with and without adjuvant chemotherapy were compared and adjusted for possible confounders using propensity score. ResultsOf 6732 breast cancer patients, 341 (5.1%) had small (≤2cm), node-negative and hormone receptor negative tumors at diagnosis. Among them, only 214 (62.8%) received adjuvant chemotherapy. Five-year overall survival was 88.1% (95% confidence interval (CI): 82.0%–94.2%) for patients receiving chemotherapy and 89.6% (95% CI: 85.1%–94.1%) for patients without chemotherapy. Chemotherapy was not associated with survival following adjustment for age, ethnicity, tumor size, tumor grade, HER2 status, lympho-vascular invasion, type of surgery and radiotherapy administration. However, chemotherapy was associated with a significant survival advantage (adjusted hazard ratio: 0.35, 95%CI: 0.14–0.91) in a subgroup of women with high-grade tumors. ConclusionAdjuvant chemotherapy does not appear to be associated with a survival benefit in women with T1N0M0, hormone receptor negative breast cancer except in those with high-grade tumors.

Are There Breast Cancer Patients with Node-Negative Small Tumours, Who Do Not Benefit from Adjuvant Systemic Therapy?

Objective: To identify subgroups of patients with pT1 pN0 breast cancer (BC) who might not profit from adjuvant systemic therapy (AST). Methods: Data of 3,774 pT1 pN0 BC patients from 17 certified BC centres within the BRENDA study group were collected between 1992 and 2008 and retrospectively analysed. Uni- and multivariate analyses were performed using Kaplan-Meier methods and Cox regression models. Results: 279 (7.4%) of the pT1 pN0 BC patients were T1a, 944 (25.0%) were T1b and 2,551 (67.6%) were T1c. There was no significant difference (p > 0.1) in recurrence-free survival (RFS)/overall survival (OAS) between patients with pT1a, pT1b, and T1c. Patients receiving any type of AST had a better outcome compared to women without AST after adjusting for age, tumour size, and intrinsic subtypes (RFS: p < 0.001; OAS: p < 0.001). AST was the most important prognostic parameter for RFS followed by intrinsic subtypes and age. Conclusion: Patients with pT1 pN0 BC profit from AST independently of molecular subtypes, tumour size, age or comorbidity, with 5-year RFS of more than 95%. The correct definition of subgroups of patients who do not need AST is still an open question.

Outcomes in patients with early-stage breast cancer who underwent a 21-gene expression assay.

Invasive disease-free survival (IDFS) rates are excellent in patients with breast cancer (BC) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), axillary lymph node-negative (LN-) tumors with a 21-gene expression assay recurrence score (RS) of 0 to 10. However, to the authors' knowledge, the outcomes among patients with an RS of 11 to 25 who are treated with endocrine therapy alone are unknown. In this retrospective single-institution study, the authors described the characteristics of patients with HR+, HER2-, LN- BC who underwent a 21-gene expression assay. In addition, among those individuals diagnosed between 2005 and 2011, we measured IDFS, recurrence-free survival, distant recurrence-free survival, and overall survival rates, focusing on patients with an RS of 11 to 25 by receipt of chemotherapy. The Kaplan-Meier method was used to estimate survival rates and multivariable Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (95% CIs). Among 1424 patients, the RS distribution was 0 to 10 in 297 patients (21%), 11 to 25 in 894 patients (63%), and >25 in 233 patients (16%); of these, 1.7%, 15%, and 73.4% of patients, respectively, received chemotherapy. With a median follow-up of 58 months, those patients with an RS of 11 to 25 had an IDFS rate at 5 years of 92.6% (95% CI, 89.6%-94.7%), which was comparable between those who received chemotherapy and those who did not. The hazard ratios of the effect of chemotherapy were 1.64 for IDFS (95% CI, 0.73-3.71), 1.46 for recurrence-free survival (95% CI, 0.41-5.23), 1.25 for distant recurrence-free survival (95% CI, 0.32-4.92), and 2.19 for overall survival (95% CI, 0.44-11.0). The results of the current study demonstrate similar outcomes with or without chemotherapy in patients with HR+, HER2-, LN- BC who have an RS of 11 to 25, but a benefit from chemotherapy in this group cannot be ruled out. Cancer 2017;123:2422-31. © 2017 American Cancer Society.