Incidence Of Distant Recurrence Research Articles

159P The impact of the extent of the type of primary breast cancer (BC) surgery from the analysis of historical Italian trials

Breast-conserving surgery (BCS) is the treatment of choice for women with early-stage BC. Several studies indicated a better outcome in patients undergoing BCS plus radiotherapy (RT) in comparison with mastectomy (MAST) +/- RT (PMID:33950173, 27344114). Indeed, in comparison with MAST, BCS reduces the extent of surgery, but the addition of radiotherapy (RT) makes it hard to understand whether the differences in outcome may be attributed to the extent of the surgery only. We performed a competing risks re-analysis in terms of dynamics and crude cumulative incidence (CCI), of distant recurrence free survival (DRFS) from two historical randomized clinical trials which of the Istituto Nazionale dei Tumori of Milan: the “Milan 1” trial (n = 701; 1973-1980, PMID:7015141) which compared MAST with BCS plus RT (BCS+RT) and the “Milan 3” trial (n = 567; 1987-1989, PMID: 8387637) which adopted the same surgical conservative approach with (BCS +RT) or without (BCS -RT) RT. Clinical features such as primary tumour size, axillary lymph node status (N) and menopausal status were considered. Concerning distant recurrence (DR) dynamics in Milan 1 trial, evidence of a different intensity of cause-specific hazard was found among subgroups related to surgery and lymph-node status (test of interaction effect: P=0.005), though with similar multi-peaked hazard patterns. Indeed, we observed that a MAST-related worse outcome is present in women with positive N (N+). Analysis of CCI reveals that, for the subgroup of N+ patients in Milan 3 trial, removal of RT from BCS (BCS -RT) results in 30% higher incidence of DR, comparable to the difference between MAST N+ and BCS+RT N+ patients in the Milan 1 trial. In this re-analysis of historical randomized clinical trials, we report that the worse outcome of MAST in comparison with BCS may be mainly attributed to higher extensive surgery and that the effect of the extent of the surgery without RT is mostly confined to patients with N+ BC. The effect of RT, as assessed by the re-analysis of Milan 3 trial, is likely related to a combined effect of the control of local recurrences, and the potential systemic effect of RT.

Multimodal treatments for resectable esophagogastric junction cancer: A Bayesian network meta-analysis.

To comprehensively investigate the optimal multimodal treatment of resectable esophagogastric junction (EGJ) cancer. PubMed, Embase, Cochrane Library and Web of Science were searched until March 11, 2022. The outcomes were overall survival (OS), locoregional and distant recurrence, and R0 resection. Network plots, forest plots and league tables were drawn for each outcome. Rank probabilities for different treatments in each outcome were also depicted. A total of 23 studies with 18,319 EGJ participants were included. No significant differences in OS between any two of the 6 treatments. Perioperative chemoradiotherapy (pCRT) had the highest probability (36.03%) to be the optimal treatment as regards OS. Patients undergoing pCRT had a significantly lower incidence of locoregional recurrence than those undergoing adjuvant chemotherapy (aCT), neoadjuvant chemotherapy (nCT), perioperative chemotherapy (pCT), or surgery alone (S). Patients with pCRT had the greatest likelihood (68.86%) to have the lowest incidence of locoregional recurrence. Comparable impacts of the 6 treatments on the incidence of distant recurrence, and pCRT was most likely (46.65%) to be the optimal treatment with respect to distant recurrence. Neoadjuvant CRT (nCRT) was associated with a significantly increased incidence of R0 resection compared with nCT or S, and nCRT had the highest probability (97.68%) to be the best therapy regarding R0 resection. For patients with resectable EGJ cancer, pCRT may be the optimal multimodal treatment regarding survival and recurrence.

Preoperative controlling nutritional status score predicts systemic disease recurrence in patients with resectable biliary tract cancer.

This study aimed to evaluate the association between the preoperative Controlling Nutritional Status (CONUT) score, survival outcomes, and recurrence pattern in patients with resectable biliary tract cancer (BTC). A total of 224 BTC patients (gallbladder, n=69; intrahepatic bile ducts, n=26; perihilar bile ducts, n=72; distal bile duct, n=57) who underwent surgery with curative intent were enrolled. The best cutoff point of the preoperative CONUT score in discriminating survival was determined using χ2 scores. The sites of recurrence were subclassified as locoregional or distant. Patients were subdivided into the CONUT-low (score ≤ 3, n=156) and the CONUT-high (score > 3; n=68) groups. In-hospital mortality occurred more frequently in the CONUT-high group than in the CONUT-low group (7.4% vs. 1.3%; p=0.028). A high preoperative CONUT score was independently associated with worse overall survival (hazard ratio [HR] 1.906, p=0.001), worse disease-specific survival (HR 1.840, p=0.006), and worse recurrence-free survival (HR 1.680, p=0.005). Recurrence developed in 110 (49.1%) patients. A high preoperative CONUT score was independently associated with a higher risk of distant recurrence (HR 2.245, p=0.001), but not locoregional recurrence. The incidences of distant recurrence at 5 years were 55.4% and 34.2% in the CONUT-high and CONUT-low groups, respectively (p=0.001). The preoperative CONUT score independently predicts survival outcomes and may serve as a surrogate marker of aggressive systemic disease recurrence in patients with resectable BTC.

Difference between carbohydrate antigen 19-9 and fluorine-18 fluorodeoxyglucose positron emission tomography in evaluating the treatment efficacy of neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma: Results of a dual-center study.

BackgroundAn accurate evaluation of neoadjuvant treatment is important to maximize the prognostic benefit of this strategy in each individual patient. The main aim of the present study is to investigate the difference between carbohydrate antigen 19‐9 and fluorine‐18 fluorodeoxyglucose positron emission tomography (FDG‐PET) in evaluating the response to neoadjuvant treatment for resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC) patients.MethodsPancreatic ductal adenocarcinoma patients with positive standard uptake values (SUV) on FDG‐PET before neoadjuvant chemoradiotherapy (NACRT) were enrolled (n = 141). In all patients, CA19‐9 and FDG‐PET were evaluated before the initiation of and after the completion of NACRT. The statuses of CA19‐9 and FDG uptake alterations during NACRT were assessed in association with survival and tumor recurrence profiles.ResultsA favorable response in each CA19‐9 and FDG‐PET was significantly related to better survival, respectively, than the unfavorable response (44.3% vs 19.5%, P < .001 and 45.8% vs 24.6%, P < .001). The status of CA19‐9 was significantly associated with the incidence of distant recurrence whereas the status of FDG‐PET was significantly associated with the incidence of local recurrence, and only patients with a favorable response in both CA19‐9 and PET statuses showed a significantly better survival than the others (5‐year survival: 56% vs 24%, P < .001), and those with unfavorable response in either of CA19‐9 or PET status showed similar poor survival to those with unfavorable in both (P = .164).ConclusionCA19‐9 and PET evaluation provided oncologically different risk assessments in terms of tumor recurrence profile, and favorable response in both CA19‐9 and FDG‐PET were necessary to achieve prognostic benefit from NACRT.

Clinical implications of the serum CA19-9 level in “biological borderline resectability” and “biological downstaging” in the setting of preoperative chemoradiation therapy for pancreatic cancer

BackgroundBiological factors are emphasized in borderline resectable pancreatic cancer (BRPC), and CA19-9 is an important factor for biological borderline resectability (b-BR). The aim of this study was to investigate the cut-off value of CA19-9 for biological borderline resectability and “biological downstaging” in chemoradiation therapy (CRT) for pancreatic cancer (PC). MethodsA total of 407 patients with anatomically resectable PC (a-R) and BRPC (a-BR) received preoperative gemcitabine-based CRT. The b-BR was determined, according to the CA19-9 value prior to preoperative CRT (pre-CA19-9), as the subgroup of a-R cases in which the survival was comparable with that in a-BR cases. “Biological downstaging” was determined based on prognostic analyses regarding the CA19-9 value after preoperative CRT (post-CA19-9) in association with the survival of R cases (a-R cases without the b-BR factor). ResultsThe 5-year survival of a-R patients with pre-CA19-9 > 120 U/mL was comparable with that of a-BR patients (44% vs 34%, p = 0.082). The survival of b-BR patients with post-CRT CA19-9 ≤ 37 U/mL (normalized) was comparably favorable with that of R patients (56% vs 65%, p = 0.369). The incidence of distant recurrence was higher in b-BR patients without post-CA19-9 normalization than in those with post-CA19-9 normalization (70% vs 50%, p = 0.003), while the incidence of local recurrence was comparable between these two groups (12% vs 13%, p = 0.986). ConclusionsBiological BRPC was determined to be an anatomically resectable disease with pre-CA19-9 > 120 U/mL, and post-CA19-9 normalization indicated “biological downstaging” in b-BR in the preoperative CRT strategy.

Economic evaluation of the oncotype DX test for hormone receptor positive (HR+) early-stage breast cancer (BC) from the Brazilian societal perspective.

e19380 Background: Selecting appropriate patients for AC (adjuvant chemotherapy) remains an important issue in BC treatment. Although AC improves clinical outcomes toxicity and economic burden is substantial. The Oncotype DX test identifies high-risk patients likely to benefit from AC who otherwise might not be identified through standard parameters (SP), and low-risk patients unlikely to benefit from AC, avoiding toxicities and inherent risks. This study estimated the incremental cost-effectiveness ratio and budget impact (BI) of Oncotype DX testing from the perspective of the Brazilian Public Health System. Methods: A Markov transitional state model was developed with 3 states: recurrence free, distant recurrence, and death. The model compared the scenario in which patients are screened by SP with a proposed scenario with Oncotype DX testing. Changes in therapeutic recommendations and cost of treatment were obtained from a prospective clinical survey at Pérola Byington Hospital. Additional data was obtained from literature. As a societal perspective analysis, medical costs (test, AC, and adverse events), costs of productivity loss, transportation and employment leave were considered. Population was estimated from BC incidence, proportion of early stage cases, and HR expression. An incremental proportion of 10% per year of patients using Oncotype DX testing was assumed. BI analysis had a 5-year horizon and cost-effectiveness a lifetime horizon (5% annual discount). Results: Oncotype DX results as identifier of a subgroup at higher risk of relapse and greater benefit with AC was dominant over SP. Oncotype DX testing resulted in clinical benefits in terms of life-years gained (0.62) and quality-adjusted life years (0.54), related to lower incidence of distant recurrence and use of AC, both of which greatly impacted quality of life. Testing resulted in economic benefits, with lower average cost per patient (−BRL 3,855). Incorporation of Oncotype DX testing resulted in potential savings reaching BRL 107 million in the 5th year stemming from the decrease in AC and consequent decrease in indirect costs. Conclusions: Patients with HR+, HER2− early stage BC may present different risks of relapse and likelihoods of benefiting from AC. With high clinical impact for patients and high economic impact for the health system, a tool that safely and accurately identifies the subgroup of patients who really needs AC is essential. Oncotype DX test incorporation in the Brazilian Public Health System should be considered.

Abstract P5-06-20: Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

Abstract &amp;lt;Background&amp;gt; The Clinical Treatment Score post-5 years (CTS5) is a prognostic tool to estimate the residual risk of distant recurrence (DR) after 5 years of endocrine therapy in postmenopausal women with estrogen receptor (ER)-positive breast cancer. (J Clin Oncol, 2018; 19: 1941-1947). CTS5 might be useful to decide the indication of extended adjuvant endocrine therapy after 5years. &amp;lt;Purpose&amp;gt; This study was conducted to elucidate the usefulness of CTS5 for the prediction of late DR in postmenopausal women with ER-positive early breast cancer treated in our department. &amp;lt;Patients and Methods&amp;gt; CTS5 was calculated in 377 postmenopausal patients with ER-positive breast cancer who underwent surgery between 2003 and 2009. They had received 5-year adjuvant endocrine therapy without DR. CTS5 is stratified into three groups; low, intermediate and high risk of DR. The relationships between CTS5 and the clinicopathological characteristics and prognosis were evaluated. &amp;lt;Results&amp;gt; According to CTS5, 202 (53.6%), 104 (27.6%) and 71 (18.8%) patients were divided into low, intermediate and high-risk of late DR groups. In the CTS5-high risk group, significantly more positive lymph nodes (p&amp;lt;0.0001), larger tumor size (p&amp;lt;0.0001), higher histological grade (p&amp;lt;0.0001), more administration of adjuvant chemotherapy (p&amp;lt;0.0001), more administration of adjuvant endocrine therapy of Aromatase inhibitor (AI) (p=0.0029), more visceral distant metastasis (p=0.0029), lower ER expression (p=0.0064) were observed. Significantly lower incidence of DR was observed in CTS5-low risk group. Thus, CTS5 was significantly prognostic for late DR. Intriguingly, in the CTS5-low risk group, administration of endocrine therapy of AI (p=0.0023), lower histological grade (HG1, 2; p=0.0011), ER high expression (TS; 6-8 p=0.0002), and positive PgR (p=0.0007) were significantly better DR-free survival (DRFS). &amp;lt;Conclusion&amp;gt; CTS5 demonstrated clinical validity for predicting late DR in this study cohort. IN the CTS5-low risk group, the incidence of late DR was significantly lower than that of in CTS5-intermediate or high risk group. The low CTS5 might be useful to decide the indication of 5-year adjuvant endocrine therapy in the postmenopausal patients with ER-positive early breast cancer. Citation Format: Wakako Tajiri, Azusa Sugii, Hideki Ijichi, Hiroki Ueo, Chinami Koga, Yoshiaki Nakamura, Masahiro Okamoto, Kennichi Taguchi, Eriko Tokunaga. Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-20.

Abstract P5-06-22: Validation of CTS5 in premenopausal breast cancer patients and the role of Ki67 among risk-stratification groups

Abstract Background: The Clinical Treatment Score at 5 years (CTS5) could be applied to identify the patients who could recommend an extension of endocrine therapy more than 5 years. In the low-risk group by CTS5, there is a limited benefit in extending endocrine therapy when patients are free from distant recurrence (DR) for 5 years. However, it raises concerns that late recurrence could occur even in the low-risk group of CTS5, and thus an issue to find factors affecting late recurrence arises in those. Furthermore, it remains unclear whether CTS5 could be adopted for premenopausal women in same context. In this study, we investigated data from patients with ER-positive breast cancer who had been free of 5-years distant recurrence. We aimed whether CTS5 is helpful to predict late DR in premenopausal and which affects late DR in the low-CTS5 group. Methods: From January 2006 to December 2013, 666 patients who had ER-positive breast cancer and had been free from 5 years DR after operation were identified. Of these, we calculated CTS5 scores using clinical variables. About 60% of the patients were premenopausal (393 of 666; 59%). To identify factors associated with late DR in the low-CTS5 group, binary logistic regression analysis was used. Results: Among all patients, late DR occurred in 25 patients. Of all patients, 402 women (60.4%) were with CTS5 low-risk group, and 10 of them (2.5%) had late DR. There were also 73 women (11%) CTS5 high-risk group, of whom 9 (12.3%) had late DR. In Kaplan-Meier analysis, the incidence of late DR was significantly increased in the high-CTS5 group (P &amp;lt; 0.001). Similarly, premenopausal women had higher rates of late DR in the high-CTS5 group (P = 0.049). In the low-CTS5 group, patients with late DR had higher Ki-67 labelling index (L.I.) compared with those without late DR (patients with Ki-67 level above 20; late DR 2/10 (22.2%) vs. without late DR 20/390 (5.1%), p = 0.027). In the multivariable analysis, Ki-67 level was found as a significant predictor for late DR in low-CTS5 group [odds ratio (OR), 11.870; CI 95%, 1.821-77.383; P = 0.010]. In other intermediate- or high-CTS5 groups, Ki67 L.I. was not associated with late DR. Conclusion: We found that CTS5 was useful to identify premenopausal women who are at risk of late DR, although CTS5 algorithm was developed by cohorts consisted of postmenopausal women. Also, the Ki67 level is helpful estimate a substantial risk of late DR in the low-CTS5 patients who are expected to have low chance of DR after 5 years endocrine therapy. Univariable and multivariable analysis in CTS5-low risk groupUnivariableMultivariableNo late DR(n=392)Late DR(n=10)p valueOR(95% CI)p valueAge49.7(±9.56)48.0(±9.32)0.5841.002(0.932-1.078)0.956pT stagepT1352(89.8%)7(70.0%)0.0451pT240(10.2%)3(30.0%)4.600(1.030-20.551)0.046pN stagepN0355(90.6%)10(100%)0.3081pN137(9.4%)0(0%)00.998Histologic gradeLow195(49.7%)6(60.0%)0.7141Intermediate182(46.4%)4(40.0%)0.381(0.085-1.719)0.210High15(3.8%)0(0%)00.998Ki67≤ 20369(94.1%)7(70.0%)0.0271&amp;gt; 2020(5.1%)2(20.0%)11.870(1.821-77.383)0.010Unknown3(0.8%)1(10.0%) Citation Format: Janghee Lee, Sung Gwe Ahn, Chihwan Cha, Soong June Bae, Dooreh Kim, Soeun Park, Joon Jeong. Validation of CTS5 in premenopausal breast cancer patients and the role of Ki67 among risk-stratification groups [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-22.

Impact of gross extrathyroidal extension into major neck structures on the prognosis of papillary thyroid carcinoma according to the American Joint Committee on Cancer eighth edition.

This study investigated the impact of gross extrathyroidal extension into major neck structures on the prognosis of papillary thyroid carcinoma according to changes in the American Joint Committee on Cancer (AJCC)/Tumor-Node-Metastasis staging system. Overall, 183 patients with gross extrathyroidal extension into major neck structures were enrolled. The 10-year disease-specific survival (DSS) of patients in each stage showed appropriate correlation and stratification with the AJCC eighth edition. However, the 10-year DSS rate in stage III was better than the expected 10-year DSS rate, according to the AJCC eighth edition. Patients in stage III were subcategorized into three new groups: stage IIIA, patients with only recurrent laryngeal nerve invasion; stage IIIB, patients with superficial invasion of the aerodigestive tract; and stage IIIC, patients with intraluminal invasion of the aerodigestive tract. The prognostic differences among these three groups and stage IVA were examined. Although the DSS rate of patients in stage IIIA was excellent, that of patients with T4a disease was worse due to the progression of aerodigestive tract infiltration. Of the four groups, the time to locoregional recurrence was the shortest for patients in stage IVA. The distant recurrent-free survival for patients in stages IIIC and IVA tended to be worse than those for patients in stages IIIA and IIIB. These results indicate that the progression of aerodigestive tract infiltration has an impact on the incidence of distant recurrence, and the presence of T4b disease has an impact on the incidence of distant and locoregional recurrences.

Incidence of Distant Recurrence in Adult Gliomas (P1.6-006)

Incidence of Distant Recurrence in Adult Gliomas (P1.6-006)

Contact of a tumour with the pleura is not associated with regional recurrence following stereotactic ablative radiotherapy for early stage non-small cell lung cancer

Background and purposeThe aim was to investigate the incidence of isolated regional failure following stereotactic ablative radiotherapy (SABR) and risk factors for recurrence. Materials and methodsEarly stage non-small cell lung cancer (NSCLC) patients treated with SABR were included in this retrospective cohort study, with isolated regional recurrence (IRR) as primary endpoint, distant recurrence (DR) and overall survival (OS) as secondary endpoints. Survival analyses were performed using the cumulative incidence function (IRR and DR) or the Kaplan–Meier method (OS) and Cox proportional hazards modelling for univariate and multivariate analyses. The prognostic effect of contact between the tumour and the pleura was investigated using the CT scans used for SABR planning. ResultsA total of 554 patients were included, of whom 494 could be analysed for IRR. The median follow-up for surviving patients was 48.1 months. Twenty-one patients developed an IRR (4%). The cumulative incidence of IRR and DR after 1-, 2-, and 5 years was 2%, 3%, 7% and 8%, 15% and 21%, respectively. Two year OS was 71%. The presence and type of pleural contact was not associated with any of the studied outcomes. ConclusionThe presence, type and length of pleural contact as surrogate for visceral pleural invasion were not predictive for outcome. Further studies focussing on risk factors for occult nodal involvement, (I)RR, distant metastases and mortality in early stage NSCLC are warranted for the development of risk adapted diagnostic, treatment and follow-up strategies as more younger, operable and fitter patients receive SABR.

Abstract P1-10-12: Differential benefit of intra-operative administration of ketorolac on breast cancer disease recurrence according to baseline body mass index

Abstract Background: According to the last estimates, 63% of the women in the US are either overweight or obese. Increased body mass index (BMI) has been recognized as a risk factor for developing breast cancer (BC) and associated with adverse survival. So far, few treatment modalities focusing on the biological features of BC patients with increased adiposity have been evaluated. In cancer patients, elevated leptin levels have been found, among others, to stimulate the Rho GTPase pathway, involved in cell adhesion and motility. Here, using a unique retrospective institutional cohort including a total of 847 BC patients, we aimed at assessing whether the intra-operative administration of ketorolac, a Non-Steroidal Anti-Inflammatory Drug (NSAID), with a recently documented Rho GTPase inhibitory activity, would be associated with an improvement in distant disease recurrence according to BMI. We further assessed in an independent series of 1,009 patients, the effect of intra-operative diclofenac, another NSAID without Rho GTPase inhibitory activity. Patients and methods: In the institutional retrospective and consecutive 'ketorolac' series of patients with primary BC surgery, 538 were treated with and 309 without a single-dose (typically 20 mg in patients under 60 kg and 30 mg in patients ≥60 kg) of intra-operative ketorolac. In the 'diclofenac' series, 789 patients were treated with intra-operative diclofenac (75 mg) and 220 without. Competing risk analysis of distant recurrences was done by crude cumulative incidence curves to be interpreted as the cumulative probability of distant metastases as first event and consistently by Fine &amp; Gray semi-parametric models on sub-distribution hazards. Subgroup analyses were conducted according to the Dixon&amp;Simon approach. These analyses were adjusted for standard clinico-pathological variables: NSAID use, tumor size, age, nodal status, grade, ER status, and BMI. The median follow-up time of the ketorolac and diclofenac cohort was 5.7 and 8.0 years, respectively. Results: In both cohorts, the administration of the NSAID was associated with younger age at diagnosis, consistent with previous reports. The administration of ketorolac was associated with decreased incidence of distant recurrences both in the unadjusted and adjusted analysis (HRadj= 0.55, 95%CI: 0.35-0.86, p=0.01). Subgroup analyses in patients with BMI&amp;lt;25 and ≥25 (overweight and obese) revealed that the effect was limited to the high BMI group of patients both in the unadjusted and adjusted analysis (HRadj= 0.58, 95%CI: 0.33-0.98). The administration of diclofenac was not associated with decreased incidence of distant recurrences, nor in the global population, neither in the BMI subgroups. Conclusion: The fact that only ketorolac but not diclofenac was associated with a significant reduction of distant recurrences in BC patients with elevated BMI could be explained by the specific Rho GTPase inhibitory effect of the R-enantiomer of ketorolac, absent in diclofenac. While this study is limited by its retrospective nature, it suggests a potentially important repositioning of ketorolac in the intra-operative treatment of BC patients with elevated BMI. A prospective study is on its way. Citation Format: Desmedt C, Demicheli R, Fornili M, Bachir I, Duca M, Viglietti G, Piccart M, Sotiriou C, Sosnowski M, Forget P, Biganzoli E. Differential benefit of intra-operative administration of ketorolac on breast cancer disease recurrence according to baseline body mass index [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 P1-10-12.

Preoperative predictors of distant recurrence in patients with clinical stage IA lung adenocarcinoma undergoing complete resection

We aimed to identify patients with clinical Stage IA lung adenocarcinoma who are at high risk for distant recurrence to preoperatively organize treatment strategies. We analyzed correlations between preoperative clinical factors and the incidence of distant recurrence in 609 patients with clinical Stage IA lung adenocarcinoma that had been completely resected at four institutions. We excluded 24 patients with only locoregional recurrence and analyzed data from 585 patients. Distant recurrence after complete resection was identified in 34 patients during a median follow-up period of 41.4 months. Multivariate Cox analysis identified solid tumor size on high-resolution computed tomography and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography/computed tomography as independent predictors for distant recurrence-free survival. Receiver operating characteristic analyses showed that solid tumor size ≥1.7 cm and the maximum standardized uptake value ≥3.3 were optimal criteria with which to detect patients at high risk for distant recurrence. In fact, 3-year distant recurrence rates were higher in patients who met the criteria for high risk (n = 85) than those who did not (n = 500) (28.1% vs. 3.7%; P < 0.001). A similar trend was also found in patients with pathological node negative. Solid tumor size on high-resolution computed tomography and the maximum standardized uptake value on F-18-fluorodeoxyglucose positron emission tomography/computed tomography were clinical predictors of distant recurrence among patients with clinical Stage IA lung adenocarcinoma. Our findings might be useful to determine personalized therapeutic strategies including systemic therapy.

Preoperative chemoradiotherapy creates an opportunity to perform sphincter preserving resection for low-lying locally advanced rectal cancer based on an oncologic outcome study.

Low-lying locally advanced rectal cancer (LARC) after preoperative chemoradiotherapy (CRT) can be surgically removed by either abdominperineal resection (APR) or sphincter preserving resection (SPR). This retrospective cohort study of 251 consecutive patients with low lying LARC who underwent CRT followed by radical surgery in a single institute, between March 2003 and November 2012, aimed to compare the oncological benefits between the two groups. 3-year disease free survival (DFS), overall survival (OS), cumulative incidence of recurrence and postoperative complications were compared between the two approaches. With median follow-up of 48.6 months, SPR group had higher 3-year DFS rate (86.4% vs 73.6%, P=0.023) and lower incidence of distant recurrence (12.0% vs 23.7%, P=0.026). The postoperative complications, incidence of local recurrence and the 3-year OS were comparable between the two groups. Pathologic T and N stage were the independent predictors for 3-year DFS (P=0.020 and P<0.001). In conclusion, our study suggest that low-lying LARC patients with a significant response to preoperative CRT can benefit from the advantage of SPR in preserving the anal sphincter function without compromising their oncologic outcome.

Histology-based Classification Predicts Pattern of Recurrence and Improves Risk Stratification in Primary Retroperitoneal Sarcoma.

To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (<10%), but early distant recurrence was common (36% at 5 years). Nomograms were developed to predict DSD, LR, and DR. Histologic type/subtype is the most important independent predictor of DSD, LR, and DR in primary retroperitoneal sarcoma. Histology predicts the pattern and incidence of LR and DR and will aid in more accurate patient counseling and selection of patients for adjuvant therapy trials.

Abstract 444: Slit2 stimulation induces a chemorepellent effect on the migration of human GBM brain tumor initiating cells

Abstract Gioblastoma (GBM) is the most common and aggressive form of primary brain tumor in adults. Despite the use of radiotherapy, chemotherapy, and surgery, survival still averages 14 months. GBM has a recurrence of almost 100% due to highly invasive brain tumor initiating cells (BTICs) left behind after surgery. As reported by our group and others, survival expectancy of GBM patients is greatly affected by tumor location. Specifically, tumors in close proximity to the lateral ventricles (LV) show a higher incidence of distant recurrence, as well as worse survival expectancy. This location is the site of the subventricular zone (SVZ), the largest neurogenic niche in the adult brain of mammals, which maintains continuous production of neural stem cells (NSCs) throughout adult life. The cause for worse prognosis in patients whose tumors are in close proximity to the SVZ is not known, but one hypothesis is that regulators of the neurogenic niche might be influencing tumor cells to become more invasive and migratory. In rodents, Slit-Robo is one of these signals which functions as a chemorepulsive ligand-receptor system involved in guiding the migration of newly generated NSCs from the SVZ to other regions of the central nervous system. Further, it has been found that Slit2 affects the migration of glioma and medulloblastoma commercial cell lines. We have previously demonstrated that primary cultured human GBM BTICs respond to slit stimulation in a chemorepellant manner. However, the robo receptor implicated in this response as well as the intracellular mechanisms affected by Slit stimulation in BTICs have not been described. Here we propose to study the effects of Slit-2 stimulation on the migration of human GBM BTICs obtained from intraoperative samples. Furthermore we evaluated the activity of Rac1 and CDC42 in GBM BTICs upon slit stimulation. We determined that Robo1 is expressed by multiple primary human GBM samples. BTICs obtained from these samples present a migratory behavior in vitro that presents a chemorepellent response upon slit2 stimulation. This chemorepellant response is not due to a decrease of cell migration as Slit2 stimulation also induced an increase in BTIC migration speed. This migratory response of BTICs to Slit2 is decreased when the Robo1 receptor is knocked down using shRNA transduction. Intracellularly, we observed that Slit2 stimulation induces a decrease in the active (GTP-bound forms) of Rac1 and CDC42. Our findings demonstrate that Slit2 can induce a chemorepellent effect on the migration of human GBM BTICs through the activation of Robo1 receptor and the subsequent modulation of the Small GTPases Rac1 and CDC42. Our results indicate that regulators of SVZ cells migration can also affect GBM cells behavior and could potentially contribute to the more aggressive behavior of SVZ-contacting GBMs. Citation Format: Hugo Guerrero-Cazares, Emily Lavell, Gabrielle Drummond, Sural Ranamukhaarachchi, Vivian Capilla-Gonzalez, Paula Schiapparelli, Alfredo Quinones-Hinojosa. Slit2 stimulation induces a chemorepellent effect on the migration of human GBM brain tumor initiating cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 444. doi:10.1158/1538-7445.AM2015-444

Predictive factors of distant recurrence after surgery in patients with clinical stage IA lung adenocarcinoma.

e18563 Background:The tumor recurrence after complete surgical resection occurs even in patients with clinical stage IA lung adenocarcinoma. The predictive factors of the distant recurrence have not been determined yet in such early stage lung adenocarcinoma patients. Methods:A total of 610 patients with clinical stage IA lung adenocarcinoma who underwent complete resection in multi-institutions were retrospectively analyzed . The correlation between clinicopathological factors andthe incidence of distant recurrence was examined. Results:Thirty six patients with distant recurrence had significant inferior overall survival. In the multivariate Cox regression analysis, solid tumor size on high resolution computed tomography (HRCT) and maximum standardized uptake (SUVmax) on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) were found to be independent predictors of distant recurrence. According to receiver operating characteristic analysis, 1.6cm or more of solid tumor size and 3.3 or more of SUVmax were indicated to be an optimal criteria to detect a high risk group for distant recurrence. In fact, distant recurrence and local recurrence were more frequently observed in patients whose solid tumor size and SUVmax met the criteria than the unmet patients (24 of 104 (20.2%) patients v.s. 12 of 506 patients (2.4%)). Conclusions:Solid tumor size on HRCT and SUVmax on FDG-PET/CT were indicated to be predictive factors of distant recurrence for the patients with clinical stage IA lung adenocarcinoma. It is highly possible that neoadjuvant chemotherapy is useful for such a high risk group.

Positive versus negative sentinel nodes in early breast cancer patients: Axillary or loco-regional relapse and survival. A study spanning 2000–2012

Sentinel Node Biopsy (SNB) is a minimally invasive alternative to elective axillary lymph node dissection (ALND) for nodal staging in early breast cancer. The present study was conducted to evaluate prognostic implications of a negative sentinel node (SN) versus a positive SN (followed by completion ALND) in a closely followed-up sample of early breast cancer patients.We studied 889 consecutive breast cancer patients operated for 908 primaries. Patients received adjuvant therapy with chemotherapy, hormone therapy and eventually trastuzumab. Radiation therapy was based on tangential radiation fields that usually included axillary level I.Median follow-up was 47 months. Axillary recurrence was seen in 1.2% (2/162) of positive SN patients, and 0.8% (5/625) of negative SN patients (p = n.s.). There was an overall 3.2% loco-regional failure rate (29/908). Incidence of distant recurrence was 3.3% (23/693) for negative SN patients, and 4.6% (9/196) for positive SN patients (p = n.s.). Overall mortality rate was 4% (8/198) for positive SN patients, while the corresponding specific mortality rate was 2.5% (5/198). For patients with negative SNs, overall mortality was 4.9% (34/693), and the specific mortality was 1.4% (19/693) (p = n.s.).We did not find significant differences in axillary/loco-regional relapse, distant metastases, disease-free interval or mortality between SN negative and SN positive patients, with a follow-up over 4 years.

Comparison Between Radical Esophagectomy and Definitive Chemoradiotherapy in Patients with Clinical T1bN0M0 Esophageal Cancer

Esophagectomy remains the mainstay treatment for clinical T1bN0M0 esophageal cancer because pathologic lymph node metastases in these patients are not negligible. Recently, chemoradiotherapy (CRT), which can preserve the esophagus, has been reported to be a promising therapeutic alternative to esophagectomy. However, to our knowledge, no comparative studies of esophagectomy and CRT have been reported in clinical T1bN0M0 esophageal cancer. A total of 173 patients with clinical T1bN0M0 squamous cell carcinoma of the thoracic esophagus were enrolled in this study, 102 of whom were treated with radical esophagectomy (S group) and 71 with definitive CRT (CRT group). Treatment results of both groups were retrospectively compared. No statistically significant difference was found in overall survival, but the S group displayed significantly better progression-free survival than the CRT group. Disease recurrence was observed in 12 S group patients and 20 CRT group patients. The incidence of distant recurrence was similar, while local recurrence and lymph node recurrence were significantly more frequent in the CRT group. In the S group, 20 patients had pathologic lymph node metastasis. The progression-free survival of patients with pathologic lymph node metastasis did not differ from those without nodal metastasis. In the CRT group, local recurrence could be controlled by salvage esophagectomy, but treatment results of lymph node recurrence were poor; only 4 of 12 patients with lymph node recurrences were cured. Selection of patients at high risk of pathologic lymph node metastasis is essential when formulating treatment decisions for clinical T1bN0M0 esophageal cancers.

The Relationship of Lymph Node Evaluation and Colorectal Cancer Survival After Curative Resection: A Multi-Institutional Study

Esophagectomy remains the mainstay treatment for clinical T1bN0M0 esophageal cancer because pathologic lymph node metastases in these patients are not negligible. Recently, chemoradiotherapy (CRT), which can preserve the esophagus, has been reported to be a promising therapeutic alternative to esophagectomy. However, to our knowledge, no comparative studies of esophagectomy and CRT have been reported in clinical T1bN0M0 esophageal cancer. A total of 173 patients with clinical T1bN0M0 squamous cell carcinoma of the thoracic esophagus were enrolled in this study, 102 of whom were treated with radical esophagectomy (S group) and 71 with definitive CRT (CRT group). Treatment results of both groups were retrospectively compared. No statistically significant difference was found in overall survival, but the S group displayed significantly better progression-free survival than the CRT group. Disease recurrence was observed in 12 S group patients and 20 CRT group patients. The incidence of distant recurrence was similar, while local recurrence and lymph node recurrence were significantly more frequent in the CRT group. In the S group, 20 patients had pathologic lymph node metastasis. The progression-free survival of patients with pathologic lymph node metastasis did not differ from those without nodal metastasis. In the CRT group, local recurrence could be controlled by salvage esophagectomy, but treatment results of lymph node recurrence were poor; only 4 of 12 patients with lymph node recurrences were cured. Selection of patients at high risk of pathologic lymph node metastasis is essential when formulating treatment decisions for clinical T1bN0M0 esophageal cancers.