Disease-free Survival HR Research Articles

Abstract PS1-22: The oncological safety of lipofilling after breast cancer surgery: A meta-analysis

Abstract INTRODUCTION Autologous fat grafting (AFG) for the purpose of breast reconstruction presents difficulties during follow-up radiological exams and the oncological potential of grafted fat is uncertain. Coleman et al in 2007 confirmed that, provided a rigorous protocol is respected, the fatty tissue could be transferred under good conditions and would not interfere with mammographic follow-up, although the issue remains controversial about the oncological safety. This study aims to analyze the oncological safety of lipofilling through a meta-analysis of the current literature. METHODS We conducted a meta-analysis to evaluate the oncological safety of AFG after breast cancer (BC) surgery. We reviewed the literature published until 07/05/2020. The outcomes were overall survival (OS), disease free-survival (DFS) and local recurrence (LR). We included RCTs, cohort studies, case-control studies that evaluated women with BC diagnosis who undergone surgery followed by reconstruction with AFG. This review was performed in accordance with the PRISMA guidelines and we searched the electronic databases of Medline, EMBASE and LILACS, using the MeSH terms for AFG and BC. There was no language restriction. Methodological quality was assessed using the Downs and Black instrument and evidence quality by GRADE. We synthesized data using the inverse variance method on the log-HR scale for time-to-event outcomes using RevMan. We assessed the presence of statistical heterogeneity using the Chi2 statistic and we investigated its extension by the use of I2 statistic. RESULTS We identified 624 references. Of these, 16 studies fulfilled our eligibility criteria and were included. Funnel plot analysis revealed no publication bias. There were 8667 patients included and their mean age was 49 years. The breast surgery indications were invasive breast carcinoma (66.1%), carcinoma in situ (18.4%) and prophylactic reasons (15,5%). Ten out of 16 studies described the technique used to perform the AFG as Coleman’s. In 9 out 16 studies there was no difference in adjuvant treatment between groups, two studies do not mention if there was any difference and in 4 studies there were different adjuvant treatments in control and intervention arms. Quality assessment resulted in 11 studies being considered ‘good’, 4 studies were considered ‘fair’ and 1 study was considered poor. The HR could be extracted from four studies and an increase of OS for lipofilling group was detected with high heterogeneity (HR 0.47, 95% CI 0.32 to 0.7, p=0.0002, 2331 patients, I2= 84%, high certainty evidence). Funnel plot analysis indicated a high risk of publication bias from one study, Krastev et al, which included 587 patients. The analysis excluding this article found no difference in OS between lipofilling group and control and publication bias was not detected (HR 0.9, 95% CI 0.53 to 1.54, p=0.71, 1744 patients, I2= 58%, high certainty evidence). The HR for DFS could be extracted from six studies and no difference was found between lipofilling group and control (HR 1.01, 95% CI 0.73 to 1.38, p=0.96, 2755 patients, I2= 0%, high certainty evidence). The HR for LR could be extracted from ten studies and no difference was found between lipofilling group and control (HR 0.86, 95% CI 0.66 to 1.12, p=0.43,6839 patients, I2= 1%, moderate certainty evidence). Funnel plot analysis indicated a publication bias from one study (Petit et al) that included only DCIS tumors. The analysis excluding this article did not demonstrate difference in results. (HR 0.8, 95% CI 0.61 to 1.05, p=0.94, 6662 patients, I2= 0%, moderate certainty evidence) CONCLUSION Based on published data, AFG is a safe technique of breast reconstruction for patients that undergone BC surgery. According to our findings, AFG did not affect OS, DFS or LR. These data have moderate to high certainty and additional studies probably will not change the current evidence. Citation Format: Rodrigo Goncalves, Bruna S Mota, Bruno Sobreiro-Lima, Marcos D Ricci, José M Soares, Jr, Edmund C Baracat, José R Filassi. The oncological safety of lipofilling after breast cancer surgery: A meta-analysis [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 PS1-22.

Chemotherapy and Surgical Resection for N1 Positive Non–small Cell Lung Cancer: Better Than Expected Outcomes

N1-positive (T1-3, N1, M0) non-small cell lung cancer (NSCLC) represents a minority distribution (∼8%) of the approximately 234,000 diagnosed cases per year. As such, there is a paucity of modern high-quality data regarding outcomes following surgically-resected, stage N1-positive NSCLC. Randomized controlled trials from more than a decade ago have demonstrated a modest 5.4% survival benefit with adjuvant chemotherapy but have included heterogenous patient populations and stage distributions. Large database analyses have questioned the role of perioperative chemotherapy in resected patients with N1 disease, but without much granular detail regarding staging, quality of surgery, and chemotherapy. This single-institution study sought to evaluate the role of perioperative chemotherapy, specifically in N1-positive NSCLC patients. Data for all patients with surgically resected N1-positive NSCLC (T1-3, N1, M0) between 2006 and 2016 were collected for this study. Patients who underwent pneumonectomy were excluded from analysis. A retrospective chart review was conducted, and comprehensive clinicopathologic data were collected relative to staging, surgery, pathologic review, and perioperative oncology treatment. After exclusion criteria were applied, 148 patients with surgically resected, N1-positive disease (T1-3, N1, M0) remained for analysis. The majority of patients underwent lobectomy (75.0%), of which 55.4% underwent minimally invasive resection. There were no differences in postoperative complications, length of stay, number of lymph nodes sampled, or mortality associated with the surgery only and surgery with adjuvant therapy subgroups. 107 patients (72.3%) received adjuvant therapy, and this was associated with higher 5-year overall survival (62.8%) and disease-free survival (45.1%) than patients who underwent surgery only (33.9% overall survival at 5 years, P = 0.01; 22.4% disease-free survival at 5 years, P = 0.04). The presence of multistation N1 nodal metastases in patients was associated with lower 5-year overall survival (22.7%) and disease-free survival (5.6%) than patients with single-station N1 nodal metastasis (60.4% overall survival at 5 years, P = 0.003; 46.0% disease-free survival at 5 years, P < 0.001). On multivariable analysis, receiving any adjuvant chemotherapy was associated with improved overall survival and disease-free survival (Overall Survival HR 0.47, P < 0.01 | Disease-Free Survival HR 0.46, P <0.01). Multistation N1 disease was associated with significantly worse disease-free survival (HR 2.11, P = 0.04). Perioperative chemotherapy was associated with improved survival in N1-positive NSCLC, and the potential magnitude of benefit exceeded 25% in this study. Patients with single-station N1 lymph node metastasis were observed to have better disease-free survival.

Abstract PO-172: Impact of African ancestry on the relationship between body mass index (BMI) and survival in early stage breast cancer: Retrospective analysis from E5103

Abstract Purpose: Both African American (AA) race and obesity are associated with worse survival in early stage breast cancer. Obesity disproportionately affects AA women, and may further racial disparities in breast cancer. Prior work investigating the intersection of race, BMI, and outcome in the large adjuvant trial E1199 found obesity to be prognostic of worse survival in White patients, with no significant impact on the disparately inferior survival outcomes seen in Black patients. However, this analysis was based on self-reported race, which neglects underlying genetic ancestry that may drive biologic differences. Here, we investigate the impact of BMI on outcomes in patients of African or European ancestry in the phase III adjuvant breast cancer trial E5103. Methods: E5103 enrolled patients with high risk, HER2 negative, early stage breast cancer to receive adjuvant doxorubicin and cyclophosphamide for 4 cycles, followed by 12 weeks of weekly paclitaxel, with or without bevacizumab. Genetic ancestry was determined on the 3,373 patients with available germline DNA, BMI, and outcome data using principal components from a genome-wide array. The primary objective was to assess the impact of BMI on disease free survival (DFS) and overall survival (OS) by ancestry. A univariate Cox proportional hazard model was used to evaluate the correlation between continuous or binary BMI and survival in AA or European Americans (EA). Results: 11.6% (n=390) of patients were genetically classified as AA and 74.6% (n=2517) as EA. Higher BMI (increment of every 5 kg/m2) was significantly associated with worse DFS (HR=1.24, p=0.006) and OS (HR=1.38, p=0.005) only in AAs, but not in EAs (DFS p=0.76, OS p=0.35). Exploring BMI categories in AAs, survival differences were most significant between patients who had morbid obesity (BMI ≥40) and those who did not (DFS HR= 2.01, p=0.009; OS HR=2.19, p=0.045). However, in EAs, even morbid obesity was not associated with survival (DFS p=0.89, OS p=0.31). In the ER+ sub-population, BMI was associated with both DFS (HR=1.29, p=0.032) and OS (HR=1.60, p=0.017) in AAs, but only with OS in EAs (HR=1.15, p=0.049). In the triple negative sub-population, there was a trend toward worse survival with increasing BMI in AAs (p=0.098), but not in EAs (p=0.62). Conclusion: In contrast to prior work based on self-reported race, we found BMI to be significantly associated with worse survival in women of African ancestry in E5103, a large adjuvant trial that reflects our current approach to curative systemic therapy in breast cancer. Categorically, this association was significant only for morbid obesity, suggesting the relationship between BMI, race, and outcome may depend on the degree of obesity. Genetic ancestry may explain biologic differences driving both higher BMI and worse outcomes resulting in racial disparities in breast cancer. Citation Format: Tarah J. Ballinger, Guanglong Jiang, Fei Shen, Kathy D. Miller, Bryan P. Schneider. Impact of African ancestry on the relationship between body mass index (BMI) and survival in early stage breast cancer: Retrospective analysis from E5103 [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-172.

Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women With Triple-Negative Breast Cancer

The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles). The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated. ClinicalTrials.gov Identifier: NCT01216111.

Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial

BackgroundLuminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes. MethodsPatients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%. ResultsOut of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]). ConclusionsNo significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.

Abstract P2-08-20: Long-term outcomes after breast conserving surgery compared with mastectomy in early breast cancer in Korea

Abstract Introduction: In some recent studies, breast conserving surgery (BCS) has been reported to improve survival rates compared with modified radical mastectomy (MRM) in early breast cancer. The purpose of this study was to evaluate long term outcome of Korean women with early breast cancer and compare the recurrence rate and overall survival according to operation methods; BCS vs MRM. Method: In this population-based study, we used information from two databases including the nationwide Korean Breast Cancer Registry (KBCR) and Asan Medical Center (AMC). We identified patients from KBCR who were diagnosed breast cancer stage 1-3 between 1998-2012 and were given either BCS or MRM regardless of axillary staging or dissection or use of adjuvant systemic therapy. To minimize confounding bias caused by variables other than operation method, we used exact match pairing of variables such as age, tumor stage and subtypes except for adjuvant radiotherapy. We compared overall survival (OS) and cancer specific survival (CSS) of BCS group and MRM group. As KBCR is multi-centered and online based registry program, we used a single center database to validate the result of KBCR. We selected patients who were diagnosed with breast cancer stage 1-3 between 1998-2008 from AMC and divided them into BCS group and MRM group. We used exact match pairing of all variables except adjuvant radiotherapy in this cohort as well and compared OS, CSS and disease-free survival (DFS). Result: Of 59121 patients who were selected from KBCR, 26581 patients received MRM and 32540 patients received BCS. 18989 patients in each group were remaining after exact match pairing. After exact matching to adjust variables other than operation method, BCS was significantly associated with better OS and CSS compared with MRM. After exact matching HR for OS and CSS were 1.47 [0.36-1.59 p&amp;lt;0.001], 1.37 [1.20-1.57 p&amp;lt;0.001] respectively. Of 8710 patients who from AMC, 2490 patients were excluded as they had unknown variables we needed to know for exact matching. 3095 patients received MRM and 3125 patients received BCS. 1790 patients in each group were remaining after exact match pairing. In this cohort after exact BCS was also significantly associated with better OS, CSS and DFS compared with MRM. After exact matching HR for OS, CSS and DFS were 1.64 [1.30-2.06 p&amp;lt;0.001], 1.71 [1.33-2.20, p&amp;lt;0.001], 1.37 [1.14-1.64, p&amp;lt;0.001] respectively. Median follow up was 88.6 month before matching and 89.2 month after matching. Conclusion: When we adjusted confounding variables by exact matching BCS showed better overall and cancer specific survival and in AMC database better recurrence free survival compared to MRM in early breast cancer patients. These results suggest that BCS is at least equivalent to mastectomy in terms of recurrence free survival and overall survival and may affect treatment decisions in early breast cancer patients. Citation Format: Hakyoung Kim, Sei Hyun Ahn, Byung Ho Son, Jong Won Lee, Il Yong Chung, Beom Seok Ko, HeeJeong Kim, Jisun Kim, Young Ju Lee, Yungil Shin, Soojeong Choi, Ho Hyun Ryu, Sae Byul Lee. Long-term outcomes after breast conserving surgery compared with mastectomy in early breast cancer in Korea [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 P2-08-20.

Sex determining region Y-box 2 is a prognostic factor for head and neck squamous cell carcinoma: Evidence from 11 published investigations.

The aim of this study was to review the published literature and investigate whether sex determining region Y-box 2 (SOX2) is a prognostic factor in head and neck squamous cell carcinoma (HNSCC) by conduct a meta-analysis. Trials were identified from the major electronic databases (MEDLINE, EMBASE, and Cochrane Library) using the key words "HNSCC" and "SOX2." The overall survival (OS), disease-specific survival (DPS), and disease-free survival (DFS) were the primary outcome measures. We identified 371 articles, 9 articles 11 studies with a total number of 1334 cases were eligible for inclusion of this meta-analysis. The results showed that OS (DPS) in low-expression group was higher than that in high-expression group. However, the difference between the two groups was not significant (hazard ratio [HR] = 1.30, 95% confidence interval [95% CI] = [0.88, 1.91]; P = 0.18), and there was great statistical heterogeneity (I2 = 66%, P = 0.002). After subgroup analysis, the HR for OS of the patients with reduced expression of SOX2 was 1.34 (95% CI = [1.04, 1.74], P = 0.03), and the heterogeneity became acceptable (I2 = 32%, P = 0.16). The HR for DFS of the patients with reduced expression of SOX2 was 1.39 (95% CI = [1.00, 1.93]; P = 0.05). The findings of this meta-analysis are indicative of that high SOX2 expression is a negative prognostic factor of HNSCC and exhibit both worse OS and DFS. However, the small sample size available for this systematic review limited the power of this quantitative meta-analysis. It may therefore be too early to place complete confidence in these results.

472P - Integration of expression rate and absolute cell counts of PD-1+ stromal tumour-infiltrating lymphocytes: Prognostic significance in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) has a poor prognosis in Asian regions and the immunotherapy targeting PD-1 is on the stage of clinical trials. This study aims to investigate the prognostic effect of PD-1 expression in intratumoral and stromal tumor-infiltrating lymphocytes (TILs) on relapse and overall survival of ESCC patients. MethodsA retrospective cohort study was conducted with recruiting 142 ESCC patients who received surgical treatment. Intratumoral and stromal PD-1 expression was tested by immunohistochemistry (IHC). ResultsThe median follow-up time was 22 months and 21.1% patients were lost of follow-up. Cell counts and expression rate of intratumoral PD1+ TILs did not show any association with disease-free survival (DFS) and overall survival (OS). Expression rate of stromal PD1+ TILs did not have a significant relationship with DFS. The patients with expression rate of stromal PD1+ TILs >20% had the median OS being 19 months and the patients with expression rate ≤20% did not achieved median OS (p = 0.034). The adjusted HR of higher expression rate was 1.49 (95%CI 0.82, 2.60, p = 0.189) for OS. ESCC patients with ≤18 stromal PD1+ TILs/HPF had the median DFS being 10 months however the patients with >18 cells/HPF had the median DFS being 48 months (p = 0.037). The adjusted HR of > 18 stromal PD1+ TILs/HPF on DFS was 0.59 (95%CI 0.35, 1.01, p = 0.055). With reference to the patients of lower expression rate/higher cell counts of stromal PD1+ TILs, patients with lower expression rate/lower cell counts, higher expression rate/higher cell counts, and higher expression rate/lower cell counts, had the adjusted HR for DFS increased to 3.73, 3.36 and 3.99 (p for trend being 0.030) and the adjusted HRs for OS increased to 2.95, 3.64 and 3.82 (p for trend being 0.015), respectively. ConclusionsIntegration of expression rate and cell counts of stromal PD1+ TILs had a significant prognostic effect in terms of relapse and overall survival. Further studies are warranted to provide reference for immunotherapy. Legal entity responsible for the studyThe authors. FundingBeijing Hospitals Authority. DisclosureAll authors have declared no conflicts of interest.

Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC).

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p &lt; .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.

HSR19-108: A Meta-Analysis of Randomized Controlled Trials (RCTs) for Efficacy and Safety of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors (VEGF-TKIs) Adjuvant Therapy in High-Risk Renal Cell Cancer (RCC)

Background: Four large RCTs (ASSURE, S-TARC, PROTECT, ATLAS) tested adjuvant VEGF-TKI therapy in high risk RCC. The results were variable for efficacy and there were concerns for increased toxicity and decline in quality of life (QoL). We performed an updated meta-analysis including results of ATLAS trial to asses a risk-benefit for adjuvant post-operative treatments in high risk RCC patients by assessing reported disease-free survival (DFS), overall survival (OS), and toxicity endpoints. Methods: Literature search was done using Medline, CENTRAL, and Embase. The DerSimonian and Laird random effects model was used to pool estimates for DFS, OS, and common side effects across the 4 trials. A subgroup analysis was performed for sunitinib alone because of its FDA approval. Heterogeneity was assessed with Cochrane Q statistic and was quantified with I2 test. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: The 4 RCTs included 4,820 patients. Adjuvant therapy with TKIs yielded no significant improvement in DFS or OS as compared to placebo (DFS HR=0.916; 95% CI, 0.832–1.009 and OS HR=1.09; 95% CI, 0.886–1.150). Separate analysis of DFS in sunitinib vs placebo did not show any benefit (2 studies, N=1,909; HR=0.90; 95% CI, 0.67–1.19). Use of TKIs was associated with significantly increased risk of drug toxicity. Increased risk of grade 3 or 4 adverse events (RR=5.110; 95% CI, 3.765–6.935), diarrhea (RR=10.725; 95% CI, 4.672–24.622), fatigue (RR=3.310; 95% CI, 1.879–5.829), hypertension (RR=4.274; 95% CI, 3.452–5.292) and palmar/plantar dysesthesia (RR=20.53; 95% CI, 9.006–46.801) was observed. There was no statistically significant heterogeneity amongst included trials. QoL endpoints were inconsistently reported. Risk of bias was low. Conclusions: This pooled analysis provides further evidence that there is no OS or DFS benefit associated with adjuvant TKI treatment. There was a significantly increased risk of grade 3 or 4 toxicity in greater than half of the patient population leading to decline in QoL during TKI therapy. Carefully selected very high-risk patients who can tolerate these agents without dose modifications may benefit from adjuvant TKI approach.

Abstract P4-14-03: Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer

Abstract Background: Early stage, hormone sensitive breast cancer is associated generally with a good prognosis, with only a minority of patients expected to die of breast cancer. Death from causes other than breast cancer can dilute the patients at risk of breast cancer events and result in over-estimation of risk of recurrence and consequently the benefit from breast cancer therapy, a so-called immortal time bias. The MA.17R trial (Goss et al 2016) evaluated the role of extending adjuvant treatment with letrozole from 5 to 10 years. Here we determine the effect of analyzing the MA.17R trial using methods accounting for competing risks. Methods: We compared conventional and competing risk methods for disease-free survival (DFS) and for distant recurrence-free survival (DRFS). In Kaplan-Meier analyses death from any cause was considered an event while cumulative incidence functions (CIFs) assumed death without recurrence to be a competing risk. The complement of the survival function (one minus the survival function) was used to estimate incidence of the primary event of interest. This was compared to estimates obtained using CIFs accounting for the occurrence of competing events. Results: Non-breast cancer death was the most common event defining DFS and DRFS. Over the course of follow-up, there was increasing discrepancy between the risk of disease recurrence measured using Kaplan-Meier and CIF. Among letrozole treated patients the estimated distant recurrence at 5 years of follow-up was 5.4% using CIF and 9.6% using Kaplan-Meier. At 10 years of follow-up, the estimated distant recurrence was 8.4% using CIF and 20.0% using Kaplan-Meier. Similar results were observed for the placebo group (8.5% vs 12.1% at 5 years and 14.8% vs 27.3% at 10 years), and in patients with baseline cardiovascular disease (see Table). Benefit from letrozole on DFS and DRFS was greater when accounting for competing risk (hazard ratio [HR] for DFS 0.66, 95%CI 0.48-0.90; DFRS HR 0.75, 0.50-1.14) compared to the conventional method (DFS HR 0.79, 0.62-0.99; DRFS HR 0.91, 0.70-1.18). In women with baseline cardiovascular risk, the benefits of extended adjuvant letrozole when considering competing risk (DFS HR 0.38, 0.16-0.89; DRFS HR 0.46, 0.16-1.35) were also greater than those observed in the conventional analysis (DFS HR 0.55, 0.32-0.93; DRFS HR 0.59, 0.33-1.04). Treatment with extended letrozole did not influence non-breast cancer death in women who died with disease recurrence (HR 1.06, 0.74 -1.50) or in those with competing risk or censored from the analysis (HR 1.05, 0.73 -1.49). Conclusion: Over the course of follow-up, estimates of DFS and DRFS differ increasingly if measured using Kaplan-Meier or CIF, with CIF estimates of risk being substantially lower. Using a competing risk model, the reduction in distant recurrence at 8 years with extended letrozole is less than 1%. Additional competing risk analyses of the MA.17 (Goss 2006) and MA.27 (Goss 2013) trials are ongoing. Cumulative incidence of disease recurrence in patients with baseline cardiovascular riskTime (years)CIF (%)1-KM (%)Letrozole11.51.534.46.555.813.8Placebo13.53.538.311.8512.520.3 Citation Format: Ethier J-L, Parulekar W, Shepherd L, Summers L, Strasser-Weippl K, Tu D, Amir E. Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-03.

Abstract PD6-04: Lifestyle intervention study (LISA) in early breast cancer (BC): An RCT of the effects of a telephone-based weight loss intervention (with educational materials) vs educational materials alone on disease-free survival (DFS)

Abstract Background: Obesity has been associated with poor BC outcomes. We investigated whether a standardized, telephone-based weight loss lifestyle intervention in recently diagnosed BC patients would lower recurrence and death rates. Methods: We conducted a multicenter RCT comparing mail-based educational material alone (control arm) or combined with a standardized, telephone-based lifestyle intervention (19 calls over 2 years, (intervention arm) that focused on diet (500-100 kcal/day deficit), physical activity (150-200 minutes of moderate-intensity activity per week) and behavior (compliance, relapse prevention) to achieve up to 10% weight loss. 338 (of 2150 planned) T1-3, N0-3, M0 ER/PgR+ BC patients with body mass index (BMI) ≥ 24 kg/m2 receiving adjuvant letrozole were randomized Aug 2007 to Jan 2010 (enrolment ended due to funding loss). Primary outcome was DFS; secondary outcome OS. Weight loss (5.3 vs 0.7% at 6 months and 3.6 vs 0.4% at 24 months in the intervention vs control arms, respectively) has been reported (JCO 2014;32:2331). At 8 years median follow-up (May 2018), DFS and OS were compared using Cox proportional hazards regression. Results: Mean age was 61.6 vs 60.4 years, mean BMI 31.4 vs 31.0 kg/m2 and adjuvant chemotherapy was received by 56.1 vs 57.5% in intervention vs controls arms respectively. T1/T2/T3 66.7/27.5/5.9% vs 61.7/33.5/3.6% and N0/1/2+ 62.6/28.7/8.8 vs 63.5/32.3/4.2% in intervention vs controls arms respectively. HER2+ in 8.8 vs 15.0% (intervention vs control). 20 of 171 (11.7%) in the lifestyle intervention arm vs 30 of 167 (18.0%) in the mail-based arm had DFS events, HR 0.71, 95%CI 0.41-1.24, p=0.23). DFS curves separated at 2 yrs; beyond 3-3.5 yrs separation approximated 5%. In a landmark DFS analysis of women alive at 24 months, DFS HR=0.68 (0.34-1.37, p=0.28). Conclusions: We identified fewer DFS events in the lifestyle intervention arm. Although loss of funding reduced sample size and lowered power, these results are consistent with a potential beneficial effect of a lifestyle intervention on DFS in postmenopausal ER/PgR+ BC patients. They provide strong support for completion of ongoing RCTs (e.g. BWEL) that will provide definitive evidence regarding the effect of lifestyle based weight loss on BC outcomes. Funded by Novartis Pharmaceuticals Inc.; Sponsored by the Ontario Clinical Oncology Group Citation Format: Goodwin PJ, Segal R, Vallis M, Ligibel JA, Pond GR, Robidoux A, Findlay BP, Gralow JR, Mukherjee SD, Levine MN, Pritchard KI. Lifestyle intervention study (LISA) in early breast cancer (BC): An RCT of the effects of a telephone-based weight loss intervention (with educational materials) vs educational materials alone on disease-free survival (DFS) [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 PD6-04.

Taxane & cyclophosphamide vs anthracycline & taxane-based chemotherapy as adjuvant treatment for breast cancer: a pooled analysis of randomized controlled trials by the Hellenic Academy of Oncology.

BackgroundAdjuvant chemotherapy has an indisputable value for early breast cancer patients. Anthracycline and taxane-based regimens (TaxAC) have not been proven superior to taxane & cyclophosphamide (TC), a less toxic combination. Our objective was to estimate the cumulative evidence for non-inferiority of TC against TaxAC, in the adjuvant setting of patients with HER2-negative, breast cancer.ResultsOverall, 7,341 patients were included in this analysis. Superiority of TaxAC or non-inferiority of TC was not established either for the overall population (DFS HR, 1.11; 95% CI, 0.95–1.30; p = 0.18), or for the node-negative patients (HR, 1.05; 95% CI, 0.82–1.34; p = 0.71). A difference in DFS of 1.28% (TC DFS, 89.04%; 95% CI, 88%–90% & TaxAC DFS, 90.32%; 95% CI, 89%–91%) was found in favor of TaxAC. Lower risk of death was not established for either treatment regimen (OS-HR, 1.02; 95% CI, 0.82–1.25; p = 0.88). Overall, the toxicity profile favored TC.ConclusionAlthough non-inferiority of TC was not proven, superiority of TaxAC is still questioned. The present analysis narrows the risk of recurrence between the treatment groups. Considering TC has a more favorable safety profile, the question as to which treatment regimen should be preferred under what circumstances, needs to be individualized according to patients’ characteristics and desires.MethodsTreatment efficacy data from The ABC trials, the Plan B trial and a trial by the Hellenic Oncology Research group (HORG) were pooled. Disease free survival (DFS) and overall survival (OS) were scrutinized. A HR of 1.18 for TC versus TaxAC was chosen to demonstrate inferiority.

Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer.

BackgroundConstitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification.MethodsWe performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided.ResultsOur validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40).ConclusionIn this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

Prognostic value of progesterone receptor in solid pseudopapillary neoplasm of the pancreas: evaluation of a pooled case series

BackgroundThe role of progesterone receptor (PR) has been reported in a series of pancreatic cysts. However, the relationship between PR and prognosis of solid pseudopapillary neoplasm of the pancreas (SPNP) has not been elucidated so far. The aim of our study was to evaluate the prognostic value of PR in SPNP.MethodsA total of 76 patients with SPNP treated in our institution from January 2012 to December 2017 were included. Demographic parameters, laboratory data, pathologic information and clinical outcomes were analyzed by the use of survival analysis. In addition, a pooled case series was performed to evaluate the results.ResultsThe institutional data included 76 patients (17 male and 59 female) ranging from 8 to 90 years (median, 30 years) in age. Kaplan-Meier survival analysis confirmed negative PR result was significantly associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) (both P < 0.001). In the pooled analysis, a total of 62 studies comprising 214 patients with SPNP were included. After multivariable cox analysis, negative PR result remained an independent prognostic factor for SPNP (DFS HR: 14.50, 95% CI: 1.98–106.05, P = 0.008; DSS HR: 9.15, 95% CI: 1.89–44.17, P = 0.006).ConclusionOur results indicated the role of PR in predicting adverse outcome of patients with SPNP and negative PR result may serve as a potential prognostic factor.

UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer

PurposeUNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). Patients and methodsTriple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)−/HER2− BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m2) or ixabepilone (40 mg/m2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. ResultsSeven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58–1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66–1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53–1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II–III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29–1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III–IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone). ConclusionAfter adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II–III lymphocytic infiltration) requires further evaluation.

Prognostic Significance of Neutrophil-to-lymphocyte Ratio in the Framework of the 8th TNM Edition for Breast Cancer.

To investigate whether neutrophil-to-lymphocyte ratio (NLR) might represent an additional biological criterion able to identify patients with worse prognosis within the 8th edition TNM prognostic staging system for breast cancer (BC). Pre-treatment NLR was retrospectively analyzed in 475 BC women prospectively followed for a mean time of 3.8 years. The optimal NLR cutoff, identified by ROC analysis, was set at 2. Elevated pre-treatment NLR was associated with worse disease-free survival (DFS) (HR=2.28) and overall survival (OS) (HR=3.39). The prognostic value of NLR was mostly evident in stage I BC (HR for DFS=2.89; HR for OS=1.30), in whom NLR significantly stratified patients who developed distant metastasis (HR= 4.62), but not local recurrence. NLR might provide important information in risk stratification, especially in stage I BC patients in whom the presence of a high NLR might raise the question as to whether they should be more aggressively managed.

Abstract P1-15-01: Final analysis of SWOG S0230/Prevention of early menopause study (POEMS)

Abstract BACKGROUND: The SWOG S0230/POEMS study demonstrated a 70% reduction in ovarian failure (OF) with goserelin coadministration during chemotherapy (CT) for ER-negative early breast cancer (BC; Moore H et al, NEJM 2015). Goserelin use was also associated with more pregnancies as well as favorable disease free survival (DFS) and overall survival (OS). Here we report the final analysis after 5 years of follow-up. METHODS: Premenopausal women age &amp;lt;50 with stage I-IIIA ER/PR-negative BC to be treated with cyclophosphamide-containing CT were randomized to receive standard CT with or without monthly goserelin 3.6 mg SQ starting at least 1 week prior to the first CT dose. The primary endpoint was OF at 2-years, defined as amenorrhea for the prior 6 months and post-menopausal FSH. Secondary endpoints included pregnancies, disease free survival (DFS) and overall survival (OS). An unplanned analysis of rate of menses recovery at 2 years (presence of menses within 6 months of the 2 year time-point or pregnancy within the first 2 years) was also conducted. OF and pregnancy endpoints were analyzed using multivariable logistic regression adjusting for stratification factors (age and CT regimen); DFS and OS were examined using multivariable Cox regression, adjusting for stratification factors and stage. Two-sided p-values are reported unless otherwise specified in accordance with protocol design. RESULTS: Among 257 randomized participants, 218 were eligible and evaluable. One hundred thirty-six eligible and evaluable patients had OF data and 186 had menstrual data. Median age was 37.7 years. Among the 136 patients with OF data, the odds ratio (OR) for OF at 2 years was 0.30 (95% CI 0.1-0.98; one-sided p=0.023) comparing CT with goserelin to standard CT alone. Among 186 patients with menstrual data, 80% recovered menses by 2 years in the goserelin arm compared with 70% in the standard arm (OR=1.74, 95% CI: 0.83-3.66, p=0.15). Pregnancies, DFS and OS are reported for all 218 eligible and evaluable patients. With a median follow-up of 5.1 years, 22% of patients in the goserelin group had at least one pregnancy compared with 12% in the standard group (OR 2.38, 95% CI 1.08-5.26, p=0.03). Cumulative incidence of pregnancy at 5 years is 23% in the goserelin arm compared with 12% in the standard group. Five-year Kaplan-Meier DFS estimates are 88% in the goserelin arm compared with 79% in the standard arm (HR=0.50, p=0.05). Five-year OS is 92% with goserelin versus 83% in the standard arm (HR=0.47, p=0.06). Including all 257 randomized patients, HR for DFS and OS are 0.67 and 0.48 (p=0.18 and p=0.05). CONCLUSION: Ovarian suppression with goserelin during chemotherapy for hormone receptor-negative breast cancer reduces OF risk and, after 5 years of follow-up, continues to be associated with more pregnancies and improved survival compared with chemotherapy without goserelin. SUPPORT: NIH/NCI grant awards CA189974, CA180888, CA180819, CA074362; AstraZeneca Citation Format: Moore HCF, Unger JM, Phillips K-A, Boyle F, Hitre E, Moseley A, Porter D, Francis PA, Goldstein LJ, Gomez HL, Vallejos CS, Partridge AH, Dakhil SR, Garcia AA, Gralow J, Lombard JM, Forbes JF, Martino S, Barlow WE, Fabian CJ, Minasian L, Meyskens FL, Gelber RD, Hortobagyi GN, Albain KS. Final analysis of SWOG S0230/Prevention of early menopause study (POEMS) [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 P1-15-01.

Clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for colorectal cancer.

867 Background: CAPOX as adjuvant chemotherapy is a standard care option for stage III and high risk stage II colorectal cancer(CRC). And then chemotherapy induced diarrhea (CID) is known as one of the dose-limiting toxicities for CAPOX. Although diverting ileostomy is useful for preventing serious complications of high risk anastomosis, it is well recognized that high ileostomy output is hard to manage. Furthermore, the effect of diverting ileostomy on CID of adjuvant chemotherapy is unclear. In this study, we addressed the clinical impact of diverting ileostomy on the dose intensity of adjuvant chemotherapy for CRC. Methods: Patients who diagnosed with stage III colon cancer and stage II or III rectal cancer after curative surgery and received CAPOX as adjuvant chemotherapy during 2011- 2014 were reviewed retrospectively. We investigated the relationship between diverting ileostomy and dose intensity, toxicities and disease-free survival (DFS). Results: 112 patients (median age 60 years, 52% male, 69% colon cancer, 63% stage III, median follow-up 47 months) were enrolled in this study. Of 112 patients, 100 patients were received chemotherapy without ileostomy (non-ileostomy group: NIG) and 12 patients were received chemotherapy with ileostomy (ileostomy group: IG). 112 Patients received 870 chemotherapy cycles. All treatment related grade 3/4 adverse events were documented in 39% of patients in NIG and 33% of patients in IG (P = 0.77). Grade 3/4 of CID occurred in 8% of patients in NIG and 8% of patients in IG (P = 1). Grade 3/4 of neutropenia were recognized in 21% of patients in NIG and 17% of patients in IG (P = 1). Average relative dose intensity (RDI) in NIG were 75.7% and 85.8% for capecitabine and oxaliplatin, respectively. Average RDI of capecitabine and oxaliplatin in IG were 76.1% and 82.7%, respectively. Significant difference of RDI of capecitabine and oxaliplatin were not shown in comparison between NIG and IG (P = 0.93, P = 0.63). The 3-year DFS rate was 85.0% in NIG and 75.0% in IG. The HR for DFS for NIG compared to IG was 1.709 (95% CI, 0.49 to 5.95; P = 0.40). Conclusions: The presence of diverting ileostomy does not affect RDI of CAPOX as adjuvant chemotherapy.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer

PurposeFor postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.MethodsIn the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.ResultsIn node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.ConclusionsThis study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.