Diet- and Lifestyle‐Based Prediction Models to Estimate Cancer Recurrence and Death in Patients With Stage III Colon Cancer (CALGB 89803/Alliance)

PURPOSE Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. METHODS Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. RESULTS Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. CONCLUSION Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Long-Term Outcome of Peripheral Blood Autologous Stem Cell Transplantation (AutoSCT) for De Novo Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Vs Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Achieving a first complete remission (CR1) is the primary goal in the treatment of AML and is an important prognostic factor for transplantation outcome in general and even more so for autologous transplantation (AutoSCT). However, there are no data for AutoSCT indicating whether the number of chemotherapy courses (1 vs 2) needed to achieve CR1 is of prognostic significance for transplantation outcome. Methods: Using the EBMT/ALWP registry, we compared transplantation outcomes of adult patients (pts) aged ≥18 years with de novo AML that underwent a peripheral blood AutoSCT in 2000-2019 in CR1 achieved following one vs two chemotherapy courses. The primary outcome was the Leukemia Free Survival (LFS). Multivariate analysis (MVA) adjusting for differences between the groups and knowns factors were performed using Cox's proportional- hazards regression model for outcomes. Results: 1825 pts were included: 1532 (84%) with one and 293 (16%) with two induction chemotherapies courses. Time from diagnosis to AutoSCT was 4.7 (3.9-5.8) vs 5.7 (4.7-7.1) months, respectively (p<0.001). Median follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years, respectively (p=0.8). Median year of transplant was 2005 (2002-2009) and 2004 (2002-2007), respectively (p<0.001). Median age was 49 (38-57) and 47 (36 -56) years (p=0.06); 54% and 57 % of both groups were male, (p=0.35). Cytogenetic risk as defined by the Medical Research Council (MRC) classification, differed significantly between the two induction groups (p<0.001). Patients with one induction had a higher percentage of favorable-risk than those with two inductions (18% vs 14%), and a lower percentage of adverse-risk cytogenetics (6% vs 13%), while 76% and 73%, respectively, had intermediate-risk cytogenetics (missing data-11percentage). Karnofsky performance score (KPS) > 90 was higher in pts receiving 1 vs 2 inductions, 71% and 58% of pts, respectively (p<0.001). The most frequent conditioning regimen for both groups was Busulfan (Bu) /Cytoxan (Cy) 50% vs 45% and Bu / Melphalan (Mel) 17% and 19%, respectively, for induction groups 1 and 2, respectively. Day 30 neutrophil engraftment incidence was 96% and 96.5%. Five -year non-relapse mortality (NRM) was 6.2% vs 6.0% for pts achieving CR1 with 2 vs 1 chemotherapy courses, respectively, and did not differ significantly (HR=1.31 (95% CI: 0.81-2.10), p=0.27). Five -year relapse incidence (RI) was higher :67.2% vs 52.3%, (HR=1.46 (95% CI: 1.25-1.72), p<0.001), while LFS and overall survival (OS) were lower for pts achieving CR1 with 2 vs 1 course of chemotherapy: 26.6% vs 41.7% (HR= 1.42 (95% CI: 1.22-1.66), p<0.001) and 36.2% vs 53.3%, (HR=1.48 (95% CI: 1.25-1.75), p<0.001), respectively (Figure). Other significant prognostic factors in MVA were adverse- compared to good risk cytogenetics and older age (per 10 years) for all AutoSCT outcome parameters including RI, NRM, LFS and OS; intermediate compared to good risk cytogenetics for RI, LFS and OS; female gender for RI and LFS ;and year of transplant for RI and OS. Conclusions: The five -year RI was higher and transplantation outcomes significantly inferior in pts with AML undergoing AutoSCT but who received two lines of chemotherapy to achieve CR1. Such pts may benefit from additional novel therapies in the conditioning or post-AutoSCT or be considered for allogeneic transplantation in an attempt to reduce their high RI and improve outcomes. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Predictors of Relapse Risk Do Not Influence Time to "Cure" in Children and Young Adults with Acute Lymphoblastic Leukaemia

After how many years from diagnosis/completing treatment should children and young adults with acute lymphoblastic leukaemia be considered "cured"? Clinical trials generally report 5 year event free survival because the risk of relapse after that time-point is very low and this is assumed to mean cure. Indeed, the risk of relapse after four years from completing therapy was <1% for patients treated on St Jude's trial Total Therapy XV and they proposed that length of follow-up should be considered to be the "time to cure". The group had previously shown that excess deaths beyond ten years in non-irradiated patients was similar to the general population whereas irradiated patients had a greater risk of excess mortality due to the development of secondary neoplasms. However, there was limited information about the time to cure and relative survival in sub-groups with variable relapse risk. We examined the long-term outcome of patients treated on an MRD stratified protocol UKALL 2003 that recruited patients between 2003-2011 to determine time to cure for the overall trial population and prognostic sub-groups defined by age, sex, immunophenotype, cytogenetics and MRD response. There were a total of 3113 patients eligible for analysis with a median follow up of 9.4 years (only 20 patients received cranial irradiation). Relative survival rates were estimated using nationwide population mortality rates as the baseline accounting for age, sex and calendar year (Office of National Statistics 2018 release). The relative survival of UKALL2003 patients compared to equivalent children in the UK population was 96% (95% CI 95.5-96.7). Relative survival did not differ by sex but was significantly worse for patients >10 years compared with younger patients (p<0.001). As expected, patients with good risk cytogenetics ( ETV6-RUNX1, and high hyperdiploidy) and negative bone marrow Ig/TCR MRD at end of induction (EOI) had better relative survival rates and lower excess mortality (all p<0.001) compared with patients who had adverse risk factors (high risk genetics and EOI MRD+). To estimate the time to a cure, we calculated the conditional probability of relapse at 12 years for patients who had survived event to the start of each follow-up year. Although the initial risk of relapse differ significantly by sex, age, MRD and genetics the risk of relapse for all subgroups quickly coalesced at around 5-6 years (Figure 1). Furthermore, the time to cure, defined as a relapse risk <1% (dashed blue line of figure), was similar across all the subgroups at 6-7 years. In conclusion, the relative survival of young patients with good risk cytogenetics and EOI MRD negative status approaches that of their normal peers. However, regardless of prognosis, the time to cure is similar across risk groups. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Randomized Phase III Trial Evaluating Radiation Following Surgical Excision for Good-Risk Ductal Carcinoma In Situ: Long-Term Report From NRG Oncology/RTOG 9804

PURPOSE To our knowledge, NRG/RTOG 9804 is the only randomized trial to assess the impact of whole breast irradiation (radiation therapy [RT]) versus observation (OBS) in women with good-risk ductal carcinoma in situ (DCIS), following lumpectomy. Long-term results focusing on ipsilateral breast recurrence (IBR), the primary outcome, are presented here. PATIENTS AND METHODS Eligible patients underwent lumpectomy for DCIS that was mammogram detected, size ≤ 2.5 cm, final margins ≥ 3 mm, and low or intermediate nuclear grade. Consented patients were randomly assigned to RT or OBS. Tamoxifen use was optional. Cumulative incidence was used to estimate IBR, log-rank test and Gray's test to compare treatments, and Fine-Gray regression for hazard ratios (HRs). RESULTS A total of six hundred thirty-six women were randomly assigned from 1999 to 2006. Median age was 58 years and mean pathologic DCIS size was 0.60 cm. Intention to use tamoxifen was balanced between arms (69%); however, actual receipt of tamoxifen varied, 58% RT versus 66% OBS ( P = .05). At 13.9 years' median follow-up, the 15-year cumulative incidence of IBR was 7.1% (95% CI, 4.0 to 11.5) with RT versus 15.1% (95% CI, 10.8 to 20.2) OBS ( P = .0007; HR = 0.36; 95% CI, 0.20 to 0.66); and for invasive LR was 5.4% (95% CI, 2.7 to 9.5) RT versus 9.5% (95% CI, 6.0 to 13.9) OBS ( P = .027; HR = 0.44; 95% CI, 0.21 to 0.91). On multivariable analysis, only RT (HR = 0.34; 95% CI, 0.19 to 0.64; P = .0007) and tamoxifen use (HR = 0.45; 95% CI, 0.25 to 0.78; P = .0047) were associated with reduced IBR. CONCLUSION RT significantly reduced all and invasive IBR for good-risk DCIS with durable results at 15 years. These results are not an absolute indication for RT but rather should inform shared patient-physician treatment decisions about ipsilateral breast risk reduction in the long term following lumpectomy.

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were stratified as: (1) Good-risk(GR)-CNA-profile (n = 51), with no deletion of IKZF1/CDKN2A/B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1 or isolated deletions of ETV6/PAX5/BTG1 or ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. (2) Poor-risk(PR)-CNA-profile (n = 34), with any deletion of ΙΚΖF1/PAR1/EBF1/RB1 or any other CΝΑ. With a median follow-up time of 49.9 months, EFS for GR-CNA-profile and PR-CNA-profile patients was 96.0% vs. 57.6% (p < 0.001). For IR-group and HR-group patients, EFS for the GR-CNA/PR-CNA subgroups was 100.0% vs. 60.0% (p < 0.001) and 88.2% vs. 55.6% (p = 0.047), respectively. Among FC-MRDd15 + patients (MRDd15 ≥ 10−4), EFS rates were 95.3% vs. 51.7% for GR-CNA/PR-CNA subjects (p < 0.001). Similarly, among FC-MRDd33 + patients (MRDd33 ≥ 10−4), EFS was 92.9% vs. 27.3% (p < 0.001) and for patients FC-MRDd33 − (MRDd33 < 10−4), EFS was 97.2% vs. 72.7% (p = 0.004), for GR-CNA/PR-CNA patients, respectively. In a multivariate analysis, the CNA-profile was the most important outcome predictor. In conclusion, the CNA-profile can establish a new genomic risk-index, identifying a distinct subgroup with increased relapse risk among the IR-group, as well as a subgroup of patients with superior prognosis among HR-patients. The CNA-profile is feasible in BFM-based protocols, further refining MRD-based risk-stratification.