Type Of Adjuvant Chemotherapy Research Articles

Clinical outcomes and impact of mismatch repair deficiency (dMMR) in patients with pT4N0 colon cancer (CC): Data from a large, consecutive, multicenter, real-world cohort.

3619 Background: T4 is widely recognized as one of the most important and independent prognostic factors in adjuvant setting for CC patients. However, the optimal management in terms of adjuvant treatment in stage II (pT4N0) as well as the impact of DNA mismatch repair deficiency (dMMR) in this subset of patients remain unclear. Here, we present a large, multicenter, real-world analysis of pT4N0 CC patients. Methods: A real-world database including pts treated at 9 Italian institutions from April 2010 to November 2023 was queried. Clinico-pathological characteristics of pts diagnosed with a stage II pT4N0 CC were analyzed. Pts were stratified according to duration of treatment, DNA mismatch repair (MMR) status, type of adjuvant chemotherapy (ACT). The primary endpoints were median relapse-free survival (RFS) and overall survival (OS). Results: A total of 380 pts was included, and outcomes data were available for 288 pts.Median age was 73 years and 49% of pts were male. 47 pts (16%) had dMMR CC, among which Lynch Syndrome was diagnosed in 19%. 10% of pts had BRAF mutant tumor, and 38% KRAS mutant tumor. After a median follow-up of 40.6 months (37.9-49.3), 3-yr RFS and 5-yr RFS were 70% and 55%, respectively, regardless treatment; 3-yr OS was 88% and 5-yr OS 73%. 154 pts (53%) received ACT: oxaliplatin (oxa)-based CT was given to 103 pts (67%), compared to 51 pts who received monotherapy (33%). Six-month ACT was given to 38 pts (74.5%) and 75 pts (72.8%) in the monotherapy and oxa-based group, respectively. Pts receiving 6-month ACT had a significant longer OS compared to those who did not receive ACT (HR 0.17; 0.08-0.34; p <.001). A trend towards improved OS was observed in pts receiving 6-month ACT versus pts receiving 3-month ACT (HR 0.46; 0.16-1.29; p 0.129). Similar results were observed in terms of RFS: 6-month ACT showed a longer RFS compared to 3-month ACT (HR 0.58; 0.32-1.05; p .068), and a significantly longer RFS compared to no-ACT (HR 0.50; 0.32-0.77; p .001). Oxa-based ACT was associated with a significant improvement in OS compared to monotherapy (HR 0.30; 0.11-0.85; p .016). Overall, pts with dMMR CC did not show a statistically significant difference in terms of OS and RFS (p .66 and .19 respectively) compared to proficient MMR pts. Conclusions: In this large real-world dataset, T4 was confirmed being a key poor prognostic factor, independently to MMR status. We observed that ACT provides large benefit in this population, and oxa-based ACT may be better than monotherapy. In addition, 6-month oxa-based ACT showed a trend towards a better outcome in comparison to 3-month ACT, even if not statistically significant. Given the retrospective nature of the study, these data should be validated in larger and prospective cohorts; however, this work may help oncologists in shared decision making in this specific subgroup of patients.

Abstract PS13-29: Four cycles of docetaxel-cyclophosphamide versus anthracycline-taxane adjuvant chemotherapy in node negative, HER2-negative breast cancer: A real-world comparison

Abstract Background: It is unknown whether four cycles of docetaxel-cyclophosphamide (DC) is an appropriate adjuvant chemotherapy option in patients with lymph node negative (LNN) and human epidermal growth factor receptor-2 (HER2) negative breast cancer in place of widely adopted anthracycline-taxane (AT) regimens. In the Canadian province of Alberta, four cycles of DC has been used preferably in the last decade as a standard adjuvant chemotherapy regimen in LNN, HER2-negative disease. We aimed to retrospectively compare the survival outcomes of patients diagnosed with LNN, HER2-negative breast cancer in Alberta who were treated with four cycles of DC as compared to those treated with an AT regimens. Methods: We identified all patients who were diagnosed with LNN, HER2-negative breast cancer treated with adjuvant chemotherapy following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with an AT regimen to up to 4 patients treated with four cycles of DC on all known/potential clinicopathologic and treatment variables (Table).We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) between the two patient groups and assessed effect of type of adjuvant chemotherapy on iDFS, BCSS and OS using Cox regression analyses.Results: Of the 726 eligible patients, 657 (90.5%) were treated with four cycles of DC and 69 (9.5%) were treated with an AT regimen. Prior to matching, women who received four cycles of DC compared to those treated with an AT regimen, were more likely to be older, have higher Charlson co-morbidity score and mastectomy for definitive surgery, and in terms of disease: earlier stage, lower grade, and HR-positive status. Matching created a group of 202 women treated with four cycles of DC and eliminated differences in clinicopathologic and treatment features between the two patient groups (Table). Four cycles of DC compared to an AT regimen was not associated with reduced iDFS (HR = 0.91, 95% CI = 0.52 to 1.6, P = 0.75), BCSS (HR = 1.10, 95% CI = 0.51 to 2.37, P = 0.8), or OS (HR = 1.01, 95% CI = 0.48 to 2.17, P = 0.96).Conclusion: In this real-life comparison, four cycles of DC as compared with an AT regimen, yielded similar survival outcomes amongst patients with LNN, HER2-negative breast cancer. Table Baseline patient and tumour characteristics of 726 patients diagnosed with LNN, HER2-negative breast cancer by type of adjuvant chemotherapy. CharacteristicAT (n=69)DC (n=657)p value*Matched DC (n=202)†p value‡Age (years) Median465347 Mean (SD; range)45.8 (9.7; 25 - 69)52.6 (9.8; 23 - 78)<0.000146 (9.4; 23 - 69)0.8BMI Median25.327.526 Mean (SD; range)27.1 (6.7;17.5 - 62)28.5 (6.6;15.6 - 64)0.127.1 (5.8;17.3- 49.4)0.9Year of diagnosis [n (%)] 2007 - 200811 (15.9%)78 (11.9%)0.2426 (13%)0.8 2009 - 201022 (31.9%)275 (41.9%)68 (33.5%) 2011 - 201236 (52.2%)304 (46.3%)108 (53%)Charlson co-morbidity score [n (%)] Mean (SD, range)0.04 (0.26; 0 - 2)0.33 (0.67; 0 - 4)<0.00010.04 (0.27; 0-2)0.9 Score > 0 - no. of patients (%)2 (2.9%)151(23%)0.00057 (3.4%)0.8 067 (97.1%)506 (77%)195 (96.6%) 11 (1.45%)97 (14.8%)4 (2%) 21 (1.45%)44 (6.7%)3 (1.4%) 309 (1.4%) 401 (0.15%)Histology [n (%)] Ductal58 (84%)479 (72.9%)0.12165 (82%)0.8 Mixed Ductal-Lobular5 (7.25%)96 (14.6%)20 (9.9%) Others6 (8.7%)82 (12.5%)17 (8.4%)T-stage [n (%)] Stage I12 (17.4%)253 (38.5%)0.000537 (18.3%)0.9 Stage II57 (82.6%)404 (61.5%)165 (81.6%)Grade differentiation [n (%)] Well differentiated026 (4%)<0.00700.9 Moderately differentiated6 (8.7%)139 (21.2%)20 (9.9%) Poorly differentiated63 (91.3%)492 (74.9%)182 (90.1%)Hormone receptor status [n (%)] Positive33 (47.8%)468 (71.2%)<0.000195 (47%)0.9 Negative36 (52.2%)189 (28.8%)107 (52.9%)Definitive breast surgery [n (%)] Breast-conserving surgery30 (43.5%)390 (59.4%)<0.0190 (44.5%)0.9 Mastectomy39 (56.5%)267 (40.6%)112 (55.5%)Radiotherapy [n (%)]36 (52.2%)397 (60.4%)0.18103 (51%)0.9Time interval to first cycle of chemotherapy (months) Median2.732.82.71 Mean (SD; range)2.86 (0.77; 1.2- 4.8)3.25 (1.38; 0 - 15)0.52.82 (0.8; 0– 5.9)0.7 No. of patients (%) 0 months ≥ – < 3 months39 (56%)404 (61.5%)0.42122 (60%)0.6 3 months ≥ – < 6 months30 (43.4%)245 (37.2%)80 (40%) ≥ 6 months08 (1.2%)0Type of adjuvant chemotherapy [n (%)] DC×4657 (100%)202 (100%) FEC×3→D×363 (91.3%) AC×4→T×43 (4.35%)TAC×63 (4.35%) Citation Format: Malek Bassam Hannouf, Atul Batra, Sasha Lupichuka. Four cycles of docetaxel-cyclophosphamide versus anthracycline-taxane adjuvant chemotherapy in node negative, HER2-negative breast cancer: A real-world comparison [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-29.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

DLL3 expression is a predictive marker of sensitivity to adjuvant chemotherapy for pulmonary LCNEC.

BackgroundThe mammalian Notch family ligands delta‐like 3 (DLL3) is reported to be a potential therapeutic target for large cell neuroendocrine carcinomas (LCNEC). The effect of DLL3 expression on LCNEC prognosis has not yet been elucidated.MethodsWe reviewed the medical records of 70 LCNEC patients undergoing surgical resection between 2001 and 2015 using a prospectively maintained database. We performed immunohistochemistry for DLL3 and investigated the correlation between the sensitivity of LCNEC to platinum‐based adjuvant chemotherapy.ResultsDLL3 expression was positive in 26 (37.1%) LCNEC patients. A total of 23 patients (32.9%) received platinum‐based adjuvant chemotherapy. Among patients with DLL3 expression‐positive tumors, no difference was found in the five‐year overall survival (OS) or recurrence‐free survival (RFS) between patients with and without adjuvant chemotherapy (surgery + chemotherapy vs. surgery alone, five‐year OS: 58.3% vs. 35.7% P = 0.36, five‐year RFS: 41.7% vs. 35.7% P = 0.74). In contrast, among patients with DLL3‐negative tumors, significantly greater five‐year OS and RFS rates were observed for patients with adjuvant chemotherapy than for those without it (surgery + chemotherapy vs. surgery alone: five‐year OS: 90.0% vs. 26.9% P<0.01, five‐year RFS: 80.0% vs. 21.7% P < 0.01). A multivariate analysis for the RFS revealed that adjuvant chemotherapy was a significant independent prognostic factor among patients with DLL3‐negative tumors (hazard ratio [HR]: 0.05, 95% confidence interval [CI]: 0.01–0.41, P < 0.01), although it was not a factor among patients with DLL3‐positive tumors (HR: 0.73, 95% CI: 0.23–2.27, P = 0.58).ConclusionsOur results revealed that DLL3 is a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC.Key pointsSignificant findings of the studyDLL3 was a predictive marker of sensitivity to platinum‐based adjuvant chemotherapy for LCNEC. Among patients with DLL3 expression‐negative LCNEC, platinum‐based adjuvant chemotherapy significantly improved the OS and RFS, although it did not do so among patients with DLL3 expression‐positive LCNEC.What this study addsOur results suggest that DLL3 expression‐positive LCNEC may be better treated with other types of adjuvant chemotherapy, such as the anti‐DLL3 therapies if these effects are confirmed by ongoing clinical research.

Optimal time interval from surgery to adjuvant chemotherapy in gastric cancer.

The effect of adjuvant chemotherapy (AC) for resected gastric cancer is well established; however, delays in treatment and its impact on clinical outcomes have not yet been determined. The current study analyzed the survival rates based on time interval (TI) between surgery and AC administration to evaluate a potential association between the two variables. Patients diagnosed with stage II–III gastric adenocarcinoma between 2009 and 2016 at the Kyung Hee University Hospital were included. Patients' data including demographics, TNM stage, types of AC, and TI retrospectively collected from surgery to the start of AC. Patients were dichotomized based on the TI, which was predetermined at 3, 4, 5, 6, 7 or 8 weeks. Median disease-free survival (DFS) and overall survival (OS) were analyzed according to TI. In total, 172 patients were identified. The median follow-up duration was 40.8 (3–109) months. The median TI was 4.1 (2.1-9.8) weeks. DFS in patients with TI ≥4 weeks (n=106, 61.6%) was significantly lower compared with patients with TI <4 weeks (n=66, 38.4%), with a median DFS of TI < vs. ≥4 weeks of 8.1 vs. 6.0 years [hazard ratio (HR)=1.80, 95% confidence interval (CI): 1.067-3.045, P=0.0277]. OS was also significantly reduced in patients with TI ≥4 weeks, favoring TI <4 weeks [median OS of TI < vs. ≥4 weeks: Not reached (NR) vs. 7.0 years, HR=2.15, 95% CI: 1.173-3.939, P=0.0133]. Other predetermined TIs were not associated with survival outcomes. The current study demonstrated that AC within 4 weeks of surgery should be recommended for gastric cancer, and delays of >4 weeks may be detrimental to patients' survival.

Body Mass Index and Hormone Receptor Status Influence Recurrence Risk in HER2-Positive Early Breast Cancer Patients

A reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2+) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting. We retrospectively evaluated 238 women with stage I to III HER2+ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ2 test. The early recurrence rate after 3 years resulted as 4.2% (40% HR+ patients and 60% HR- patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR- tumors who had also BMI≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR+ tumors and with BMI<25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P= .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P= .03). Our real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR- and have BMI≥25 might benefit from escalation approaches, whereas those who are HR+ and have BMI<25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.

Abstract GS4-07: Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial

Abstract Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (&amp;gt;2 cm vs. &amp;lt;=2 cm), histologic grade (high vs. medium vs. low vs. unknown), continuous recurrence score (RS), race, and ethnicity in the overall population and randomized treatment arms in the RS 11-25 cohort. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age (&amp;lt;/=50 years) at diagnosis. The use and type of adjuvant chemotherapy and endocrine therapy, and duration of endocrine therapy, were similar in black (vs. white) and Hispanic (vs. non-Hispanic) populations. In proportional hazards models, black race (compared with white race) was associated with worse clinical outcomes in the entire population and in those with a RS 11-25 (see table). Hispanic ethnicity was generally associated with better outcomes (compared with non-Hispanic ethnicity). For the cohort with a RS of 11-25, there was no evidence for chemotherapy benefit for any racial or ethnic group. Race (black vs.white) and clinical outcomes in proportional hazards modelsClinical endpointEntire Population (N=693 black) Hazard ratio for eventRS 11-25 (N=471 black) Hazard ratio for eveniDFS1.33 (p=0.005)1.49 (p=0.001)DRFI1.21 (p=0.28)1.60 (p=0.02)RFI1.39 (p=0.02)1.80 (p&amp;lt;0.001)OS1.52 (p=0.005)1.67 (p=0.003 Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [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 GS4-07.

Retrospective study of survival time and prognostic factors for dogs with small intestinal adenocarcinoma treated by tumor excision with or without adjuvant chemotherapy.

OBJECTIVE To estimate survival time for dogs with small intestinal adenocarcinoma (SIACA) following tumor excision with or without adjuvant chemotherapy and to identify factors associated with survival time. DESIGN Retrospective case series with a nested cohort study. ANIMALS 29 client-owned dogs with surgically resected, histologically diagnosed SIACA. PROCEDURES Medical records were reviewed and data collected regarding dog signalment; clinical signs; physical examination findings; PCV; serum total solids concentration; diagnostic imaging results; tumor size, location, and histologic characteristics (serosal extension, lymphatic invasion, surgical margins, and lymph node metastasis); type of adjuvant chemotherapy; NSAID administration; and survival time. Variables were assessed for associations with survival time and hazard rate via Kaplan-Meier and Cox proportional hazards analyses. RESULTS Overall median survival time for dogs with SIACA following tumor excision was 544 days (95% confidence interval, 369 to 719 days). Based on Kaplan-Meier estimates, the 1- and 2-year survival rates were 60% and 36%, respectively. On multivariate analysis, only age category was an independent predictor of survival over the follow-up period. Dogs < 8 years of age had a significantly longer median survival time (1,193 days) than dogs ≥ 8 years (488 days). Lymph node metastasis, adjuvant chemotherapy, NSAID administration, and other assessed variables were not associated with survival time. CONCLUSIONS AND CLINICAL RELEVANCE Findings suggested that SIACA in dogs carries a fair prognosis following excision, even when lymph node metastasis is present. Prospective studies are warranted to better characterize the effects of adjuvant chemotherapy or NSAID administration on survival time.

Real life adjuvant chemotherapy uptake and survival in patients with non-small cell lung cancer after complete resection

Objectives: Adjuvant chemotherapy (AC) in non-small cell lung cancer (NSCLC) has become a standard of care in patients with stages IIA, IIB, and IIIA after complete tumor resection. Utilization and outcome of AC in routine practice is described in a few studies, with non-conclusive results.Materials and methods: This retrospective study included consecutive patients with NSCLC who underwent curative-intent surgery. Data of AC uptake in stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and reasons of AC omission were evaluated according to medical records. Mortality risk among patients treated with surgery (only) and different types of AC in routine practice was compared.Results: AC was applied to 79% of patients with stages IB (tumor of ≥4 cm in diameter), II, and IIIA, and was associated with an improved median of overall survival (HR = 0.69; 95% CI = 0.44–1.06). Significantly longer survival was achieved in the sub-group treated with platinum and oral vinorelbine (HR = 0.575, 95% CI = 0.339–0.974), and the longest survival was among patients treated with oral vinorelbine and cisplatin (HR = 0.371, 95% CI = 0.168–0.820).Conclusions: AC utilization should be based on co-operation between surgeons, pneumo-oncologists, and patients. Rational use of AC offers better survival in routine practice.

Type of adjuvant chemotherapy and treatment frequency in survival outcome of patients with colorectal liver metastases who underwent liver metastasectomy: an 8-year cohort study in Taiwan.

The role of adjuvant chemotherapy (ACT) in treating patients who have colorectal liver metastases (CLM) and undergo liver metastasectomy (LMS) is unclear in this patient population. We aimed to compare the mortality of patients receiving different ACT (i.e., oxaliplatin-based, irinotecan-based, and 5-fluorouracil-only (5FU)) and different treatment frequencies. We included 2583 patients with CLM who underwent LMS (including synchronous LMS [SLMS] and metachronous LMS [MLMS]) in this retrospective cohort study. We used Cox proportional hazard model to obtain hazard ratios (HRs) for mortality. The reference group was 5FU-only ACT when comparing ACT type and the reference group was treatment for ≤ 3 times when comparing ACT frequency. In SLMS patients, oxaliplatin-based ACT (HR = 0.78) and receiving ACT for ≥ 4 times (4-6 times, HR = 0.61; 7-9 times, HR = 0.69; 10-12 times, HR = 0.66) were associated with lower risk of mortality. In MLMS patients, oxaliplatin-based ACT (HR = 0.52), irinotecan-based ACT (HR = 0.64), and receiving ACT for 10-12 times (HR = 0.65) were associated with lower risk of mortality. In SLMS and MLMS patients, patients who received oxaliplatin-based ACT were more likely to survive than patients who received 5FU-only ACT. In MLMS patients, patients who received irinotecan-based ACT were also more likely to survive than those who received 5FU-only ACT. We recommend a course of at least four to six times of ACT after LMS in this patient population.

Current adjuvant treatment modalities for gastric cancer: From history to the future.

The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world. The adjuvant treatment recommendation is generally chemoradiotherapy in the United States, perioperative chemotherapy in the United Kingdom and parts of Europe, and chemotherapy in Asia. These options mainly rely on the United States Intergroup-0116, United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy, and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials. However, the benefits were evident for only certain patients, which were not very homogeneous regarding the type of surgery, chemotherapy regimens, and stage of disease. Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate. Regardless of the extent of surgery, multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement. Moreover, in the era of individualized treatment for most of the other cancer types, identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation. The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients.

Time to initiation of adjuvant chemotherapy in patients with rapidly proliferating early breast cancer

To evaluate the optimal time interval from definitive surgery to commencing chemotherapy in early breast cancer (EBC). The relationship between time to initiation of adjuvant chemotherapy (TTC), calculated in weeks, and disease-free (DFS) or overall survival (OS), was assessed in 921 EBC patients with rapidly proliferating tumours (thymidine labelling index >3% or G3 or Ki67 >20%), randomised in a phase III clinical trial (NCT01031030) to receive chemotherapy with or without anthracyclines (epirubicin→cyclophosphamide, methotrexate and fluorouracil (CMF) versus CMF→epirubicin versus CMF). DFS, OS and 95% confidence intervals (95% confidence interval (CI)) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation with nodal involvement, oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumour size. At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase in the risk of relapse: hazard ratio (HR) 1.15 (95% CI 1.02-1.30, p=0.019). Using a backward elimination procedure, TTC, tumour size and nodal involvement remained significantly associated with DFS. A time-dependent receiver-operating characteristic (ROC) curve analysis was subsequently utilised to evaluate the best cut-off for TTC, identifying 7 weeks as the best threshold for longer OS (p=0.043): 8-year OS 88% (95% CI 85-90) for patients with a TTC <7 weeks and 78% (95% CI 68-87) for the other group. Our results confirm that a shorter TTC may reduce relapses and possibly also improve clinical outcome in patients with highly proliferating EBC.

Minimal deviation mucinous adenocarcinoma of the uterine cervix that proved difficult to differentiate from endometrial cancer: A case report.

Minimal deviation adenocarcinoma (MDA), also known as adenoma malignum of the uterine cervix, accounts for only ~1% of uterine cervical adenocarcinomas. Adenoma malignum of the uterine cervix was initially described by Gusserow in 1870. Using magnetic resonance imaging (MRI), MDA appears as multilocular lesions with solid components that extend from the endocervical glands to the deep cervical stroma. Cytological evaluation and biopsies have low detection rates, therefore, it is difficult to diagnose MDA accurately prior to treatment. The current study describes a rare case of MDA that was difficult to differentiate from endometrial adenocarcinoma of the corpus uteri preoperatively, as the endometrial biopsy results suggested a well-differentiated endometrioid adenocarcinoma and MRI did not show typical images for MDA. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed under the diagnosis of endometrial cancer, and the mass was subsequently diagnosed as MDA of the uterine cervix by pathological examination of the hysterectomy specimen. Postoperatively, although two types of adjuvant chemotherapy were performed, the remaining tumor continued to grow, causing obstruction of the bilateral ureters and leading to bilateral hydronephrosis. The patient is currently alive with the disease 10 months following the surgery.

263PD - Time to Initiation of Adjuvant Chemotherapy in Patients with Rapidly Proliferating Early Breast Cancer

ABSTRACT Introduction: The optimal time from surgery to commencing chemotherapy in early breast cancer (EBC) remains unclear. We assessed the influence of time to initiation of adjuvant chemotherapy (TTC) on the outcome of EBC patients enrolled onto a phase III clinical trial (NCT01031030). Methods: The relationship between TTC, calculated as the time (in weeks) from definitive surgery to initiation of adjuvant chemotherapy, and disease-free (DFS) or overall survival (OS) was assessed in 1066 EBC patients with rapidly proliferating tumors (thymidine labeling index > 3% or G3 or Ki67 > 20%), randomized to receive adjuvant chemotherapy with or without anthracyclines (epirubicin → CMF vs CMF → epirubicin vs CMF). DFS, OS and their 95% confidence intervals (95% CI) were calculated by the Kaplan-Meier method. Multivariate Cox analysis was performed in relation to nodal involvement, estrogen receptor and HER2 status, Ki67 value, type of adjuvant chemotherapy, menopausal status and tumor size. Results: Information on TTC was available for 713 women. At a median follow-up of 105 months (range 2-188), a prolonged TTC resulted in a significant increase of 16% in the risk of relapse (95% CI 1.03–1.30, p = 0.016) in a multivariable Cox regression model (Table 1). The impact on OS was not significant. Using a backward elimination procedure, TTC, tumor size and nodal involvement remained significantly associated with DFS (Hazard ratio [HR] = 1.15, 95% CI 1.02-1.29, p = 0.018; HR = 1.44, 95% CI 1.08-1.92, p = 0.012; HR = 1.44, 95% CI 1.08-1.92, p = 0.012, respectively). Again, nodal involvement and Ki67 were associated with OS (HR = 1.66, 95% CI 1.11-2.49, p = 0.014; HR = 1.63, 95% CI 1.03-2.59, p = 0.039, respectively). DFS OS HR (95% CI) p HR (95% CI) p TTC 1.16 (1.03–1.30) 0.016 1.14 (0.97–1.35) 0.121 Age 0.99 (0.97–1.02) 0.829 0.99 (0.96–1.03) 0.615 ER Positive 1.00 1.00 Negative 1.20 (0.89–1.61) 0.242 1.20 (0.78–1.84) 0.397 HER2 Positive 1.00 1.00 Negative 0.99 (0.73–1.33) 0.929 0.92 (0.60–1.42) 0.713 Lymph node status Negative 1.00 1.00 Positive 1.53 (1.14–2.04) 0.004 1.71 (1.13–2.59) 0.011 Menopausal status Premenopausal 1.00 1.00 Postmenopausal 1.32 (0.85–2.04) 0.219 1.56 (0.82–2.97) 0.177 Tumor size 1.00 1.00 ≥2 cm 1.41 (1.05–1.88) 0.020 1.44 (0.95–2.18) 0.085 Ki67 ≤20% 1.00 1.00 >20% 1.06 (0.77–1.44) 0.724 1.54 (0.96–2.48) 0.073 Treatment arm E»CMF 0.72 (0.49–1.04) 0.079 0.69 (0.41–1.16) 0.161 CMF»E 0.79 (0.55–1.14) 0.202 0.75 (0.45–1.25) 0.273 CMF 1.00 1.00 Conclusions: Our results suggest that patients with rapidly proliferating EBC should be treated as soon as possible once their recovery from surgery is complete. Disclosure: All authors have declared no conflicts of interest.

Effectiveness of different treatment modalities for the management of adult-onset granulosa cell tumours of the ovary (primary and recurrent).

Granulosa cell tumour is a rare gynaecological tumour of the ovary with recurrences many years after initial diagnosis and treatment. Evidence-based management of granulosa cell tumour of the ovary is limited, and treatment has not been standardised. Surgery, including fertility-sparing procedures for young women, has traditionally been the standard treatment. Adjuvant treatments following surgery have been based on non-randomised trials. A combination of bleomycin, etoposide and cisplatin (BEP) has traditionally been used for treatment of advanced and/or recurrent disease that cannot be optimally managed surgically. To evaluate the effectiveness and safety of different treatment modalities offered in current practice for the management of primary, residual and recurrent adult-onset granulosa cell tumours (GCTs) of the ovary. We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to December 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. We searched for randomised controlled trials (RCTs), quasi-RCTs and observational studies that examined women with adult-onset granulosa cell tumours of the ovary (primary and recurrent). For non-randomised studies, we included studies that used multivariate analysis to adjust for baseline characteristics. Two review authors independently abstracted data and assessed risk of bias. Studies were heterogeneous with respect to treatment comparisons, so data were not synthesised in meta-analyses, and methods for assessing heterogeneity were not needed. Risk of bias in included studies was assessed by using the six core items used to assess RCTs and by evaluating four additional criteria specifically addressing risk of bias in non-randomised studies. Five retrospective cohort studies (535 women with a diagnosis of GCT) that used appropriate statistical methods for adjustment were included in the review.Two studies, which carried out multivariate analyses that attempted to identify factors associated with better outcomes (in terms of overall survival), reported no apparent evidence of a difference in overall survival between surgical approaches, whether a participant underwent lymphadenectomy or received adjuvant chemotherapy or radiotherapy. Only percentage of survival for all participants combined was reported in two trials and was not reported at all in one study.One study showed that women who received postoperative radiotherapy had lower risk of disease recurrence compared with those who underwent surgery alone (adjusted hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.1 to 0.6, P value 0.04). Three studies reportedthat there was no evidence of differences in disease recurrence based on execution and type of adjuvant chemotherapy or on type of surgery or surgical approach, other than that surgical staging may be important. One study described no apparent evidence of a difference in disease recurrence between fertility-sparing surgery and conventional surgery. Recurrence-free survival was not reported in one study.Toxicity and adverse event data were incompletely reported in the five studies. None of the five studies reported on quality of life (QoL). All studies were at very high risk of bias. One study showed a lower recurrence rate with the use of adjuvant radiotherapy, although this study was at high risk of bias and the results should be interpreted with caution. After evaluating the five small retrospective studies, we are unable to reach any firm conclusions as to the effectiveness and safety of different types and approaches of surgery, including conservative surgery, as well as adjuvant chemotherapy or radiotherapy, for management of GCTs of the ovary. The available evidence is very limited, and the review provides only low-quality evidence. Further research is very likely to have an important impact on our confidence in the estimate of effect and may alter our findings.Ideally, multinational RCTs are needed to answer these questions. The disease is relatively rare and generally has a good prognosis. RCTs are challenging to conduct, but three ongoing trials have been identified, demonstrating that they are feasible, although two of these studies are single-arm trials. The study that may be able to provide answers to the question of which chemotherapeutic regimen should be selected for management of sex cord stromal tumours is an ongoing, randomised, phase 2 study, led by the Gynaecological Oncology Group to compare the efficacy of carboplatin and paclitaxel versus standard BEP. These investigators are also looking into the value of inhibin A and inhibin B as predictive biomarkers. Additional trials are required to assess toxicity and QoL associated with different treatment regimens as well as the safety of conservative surgical options.

Abstract P5-10-11: Clinical significance of microRNA expression as a prognostic factor in early N+ breast cancer (BC)

Abstract Background: microRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. In the present study, we describe miRNA expression in early node-positive BC and identify a 8-miRNA score that could contribute to prognosis assessment. Methods: First, microarray analysis was performed using RNA samples extracted from primary breast cancer. The expression of miRNAs was analyzed by RT-qPCR using the TaqMan Arrays from Applied Biosystems. After a suitable normalization of the 677 miRNAs analyzed, 123 presented a good correlation between their levels of expression in frozen tissue and paraffin tissue. A supervised analysis was done in order to identify MIR that could predict relapse. Results: 172 patients with node-positive chemotherapy-treated early BC were included in the present study. The median age at diagnosis was (53.7) years, 128 cases (74.4%) had positive estrogen receptor, and 163 patients (94,7%) received adjuvant chemotherapy. After a median follow up of 8,1 years, 71p (41.2%) relapsed. Supervised analyses identified 8 microRNAs (has miR-30e, miR-30a, miR-21, miR-210, miR-93, miR-150, miR-99b, miR-572) associated with higher risk of relapse (5 year PFS 50% vs 90%, HR 3.75, 95% CI 2.27–6.19) and with estimated overall survival (median not reached, HR 4.51, 95% CI 2.36–8.61). Interestingly, miRNAs defined 2 prognostic groups (high and low risk) regardless of type of adjuvant chemotherapy (with or without anthracyclines) and histological subtype (luminal A, B or triple negative). Conclusions: This study suggests that miRNA expression could contribute to assess molecular prognosis of breast cancer and identifies clusters of miRNAs that could improve outcome prediction. A validation study in node-negative and triple negative disease is planned. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-11.

Omission of lymph nodal dissection in women with early breast cancer and positive sentinel lymph node biopsy: reflections of a medical oncologist

The majority of women with operable breast cancer are candidates for adjuvant systemic therapies, including chemotherapy, endocrine therapy and biologically targeted agents. The decision to administer adjuvant treatments is based on factors related to the patient (e.g., age, comorbidity and patient preference) and to the tumor. When a medical oncologist considers the latter set of factors, the attempt is twofold: to identify predictors of the efficacy of specific forms of treatment and to estimate the risk that a patient will develop local or distant relapse (i.e., prognostic factors). These two elements are crucial in predicting the possible benefits of adjuvant therapy and to make appropriate estimates of how benefits counteract the potential treatment-related harms. In particular, owing to short-term and, mostly, longterm potential side effects, the decision to include chemotherapy in the adjuvant program is often a challenging one. For many years, medical oncologists have identif ied metastatic spread to the axilla as one of the strongest surrogates of the likelihood of a tumor to develop metastases during postsurgical follow-up, and, consequently, one of the most important indications for aggressive adjuvant treatments. The risk of relapsing and dying from breast cancer increases significantly with each additional positive axillary lymph node (ALN) [1]. However, ALN involvement is often considered a dichotomous state (positive or negative) with respect to prognosis, and, on average, the type of adjuvant chemotherapy is not chosen on the basis of the absolute number of positive ALNs. In the USA, the National Cancer Institute [2] and the National Comprehensive Cancer Network guidelines [101] suggest the consideration of chemotherapy for all patients with at least one positive ALN. In addition to this, if chemotherapy is indicated for a patient because her risk of developing metastases is beyond a certain threshold, the most effective regimen should be chosen, regardless of the amount of risk associated [3]. So, let us review the simple terms of this equation: at least one positive ALN is enough to consider adjuvant chemotherapy; and the type of chemotherapy should be the same, regardless of whether that patient has one or multiple involved lymph nodes. If one

Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer.

454 Background: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERα) transcriptional activity in breast cancer. The mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR), suggesting these SNPs were functionally significant. In colon cancer (CC), ERβ expression has been shown to be predominant with low levels of ERα also expressed. ERα stimulates cell proliferation, while ERβ negatively regulates the estrogen-dependent activity of ERα. Based on these previous findings, we hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in stage II and III CC. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs (range 22–78 yrs)) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK). Results: The minor allele of LMTK3 rs9989661 (C; frequency=30.5%) showed significantly longer median TTR (5.9 vs 12.2+ yrs; HR: 0.41, 95%CI: 0.15-1.18, log-rank p=0.086; univariate analysis) in female CC patients. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.25, 95%CI: 0.077-0.778, Wald test p=0.017). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This is the first report demonstrating LMTK3 rs9989661 associations with gender-related TTR in CC. We hypothesize that there is an ERα-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERβ. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.

Use of genetic variants of LMTK3 to predict tumor recurrence in female localized gastric adenocarcinoma.

63 Background: Previous study suggests that high basal Lemur Tyrosine Kinase 3 (LMTK3) expression was associated with advanced stage of primary breast cancers as well as decreased overall and disease-free survival. LMTK3 was also found overexpressed in gastric cancer. Our previous data showed the mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR) in colon cancer (CC). We hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in a cohort of localized gastric cancer patients. Methods: Either blood or FFPE tissue specimens obtained from 137 localized (stage Ib-IV) GA patients (54 females and 83 males) were included in this study. All patients were treated with surgery alone or surgery and adjuvant (radio)-chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC), the Los Angeles County/University of Southern California Medical Center, or the Memorial Sloan-Kettering Cancer Center from 1992 to 2008. The median follow-up was 3.3 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. Results: LMTK3 rs9989661 was significantly associated with TTR in females GA patients. Female patients with minor C allele (TC or CC) (n=25) of LMTK3 rs9989661 showed significantly longer median TTR=7.0 (95%CI: 2.1-8.3+) years compared to those harboring homozygous TT genotype. (n=28), TTR=1.7 (95%CI: 0.7-7.0+) years.( log-rank p=0.025; univariate analysis). After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.14, 95%CI: 0.02-0.94, multivariate Wald p value = 0.043 in the dominant model). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This pilot study demonstrating LMTK3 rs9989661 may be potential molecular marker to predict TTR in female localized GA. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.

The utility of Aspirin in Dukes C and High Risk Dukes B Colorectal cancer--the ASCOLT study: study protocol for a randomized controlled trial.

BackgroundHigh quality evidence indicates that aspirin is effective in reducing colorectal polyps; and numerous epidemiological studies point towards an ability to prevent colorectal cancer. However the role of Aspirin as an adjuvant agent in patients with established cancers remains to be defined. Recently a nested case-control study within the Nurses Health cohort suggested that the initiation of Aspirin after the diagnosis of colon cancer reduced overall colorectal cancer specific mortality. Although this data is supportive of Aspirin's biological activity in this disease and possible role in adjuvant therapy, it needs to be confirmed in a randomized prospective trial.Methods/DesignWe hypothesize through this randomized, placebo-controlled adjuvant study, that Aspirin in patients with dukes C or high risk dukes B colorectal cancer (ASCOLT) can improve survival in this patient population over placebo control. The primary endpoint of this study is Disease Free Survival and the secondary Endpoint is 5 yr Overall Survival. This study will randomize eligible patients with Dukes C or high risk Dukes B colorectal cancer, after completion of surgery and standard adjuvant chemotherapy (+/- radiation therapy for rectal cancer patients) to 200 mg Aspirin or Placebo for 3 years. Stratification factors include study centre, rectal or colon cancer stage, and type of adjuvant chemotherapy (exposed/not exposed to oxaliplatin). After randomization, patient will be followed up with 3 monthly assessments whilst on study drug and for a total of 5 years. Patients with active peptic ulcer disease, bleeding diathesis or on treatment with aspirin or anti-platelet agents will be excluded from the study.DiscussionThis study aims to evaluate Aspirin's role as an adjuvant treatment in colorectal cancer. If indeed found to be beneficial, because aspirin is cheap, accessible and easy to administer, it will positively impact the lives of many individuals in Asia and globally.Trials RegistrationClinicaltrials.gov: NCT00565708