Risk Of Distant Recurrence Research Articles

Uni-, Bi- or Trifocal Hepatocellular Carcinoma in Western Patients: Recurrence and Survival after Percutaneous Thermal Ablation.

Simple SummaryPercutaneous thermal ablation (PTA) is a validated treatment for small (<3 cm) hepatocellular carcinoma (HCC). Multifocality is usually reported as a strong pejorative factor. Yet, the current literature lacks data on the influence in Western patients of HCC nodule numbers on recurrence and survival after PTA. From a prospective cohort of patients who underwent PTA for <3 cm HCC, we retrospectively compared recurrence and survival, according to the number of nodules. We found that bi- and trifocal HCC significantly increased the risk of distant recurrence, especially very early (<6 months) distant recurrence. Overall survival after PTA of trifocal HCC proved to be significantly below what was expected after a curative treatment, ranging between that of BCLC A and of BCLC B patients. Liver transplantation should certainly be considered earlier in this sub-population. Reasonable hopes come from adjuvant/neoadjuvant trials based on immunotherapies alone or in combination.Multifocality is usually reported as a pejorative factor after percutaneous thermal ablation (PTA) of HCC but little is known in Western series. Recurrence and survival were extracted from a prospective database of all patients who underwent PTA for ≤3 cm HCC. From January 2015 to April 2020, we analyzed 281 patients with unifocal (n = 216), bifocal (n = 46) and trifocal (n = 16) HCC. PTA of bi- and trifocal HCC resulted in a high risk of very early (<6 months) distant recurrence (38.8% and 50%, respectively). Median RFS was 23.3 months (95% CI:18.6–30.4), 7.7 months (95% CI:5.1–11.43, p = 0.002) and 5.2 months (95% CI:3–12.3, p = 0.015), respectively, for uni-, bi- and trifocal HCC groups. In a multivariate analysis, both bifocal (HR = 2.46, p < 0.001) and trifocal (HR = 2.70, p = 0.021) vs. unifocal HCC independently predicted shorter RFS. Median OS in trifocal HCC group was 30.3 months (95 CI:19.3-not reached). Trifocal vs. unifocal HCC independently predicted shorter OS (HR = 3.30, p = 0.008), whereas bifocal vs. unifocal HCC did not (p = 0.27). Naïve patient (HR = 0.42, p = 0.007), AFP > 100 ng/mL (HR = 3.03, p = 0.008), MELD > 9 (HR = 2.84, p = 0.001) and steatotic HCC (HR = 0.12, p = 0.038) were also independent predictors of OS. In conclusion, multifocal HCCs in a Western population have a dramatically increased risk of distant recurrence. OS after PTA of trifocal HCC is significantly below what was expected after a curative treatment.

Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial.

500 Background: Gene signatures have proven successful in identifying patients with a low risk of distant recurrence who could forego chemotherapy (CT) and are currently included in international treatment guidelines for breast cancer. For the 70-gene signature (MammaPrint) an additional threshold was established within the low risk category to identify patients with an ultralow risk of distant recurrence. In independent cohorts, these patients had excellent breast cancer specific survival at 15 years, suggesting that ultralow risk cancers represent indolent disease (Esserman, JAMA Oncol 2017, Delahaye, BC Res Treat 2017). Here we evaluate survival of patients with an ultralow risk 70-gene signature who participated in the randomized phase 3 MINDACT trial (Piccart, Lancet Oncol 2021). Methods: Of the 6,693 patients enrolled in the MINDACT trial (EORTC 10041/BIG 3-04) between 2007-2011, profiling revealed an ultralow risk 70-gene signature in 1,000 patients (15%). We assessed 5- and 8-year distant metastasis free interval (DMFI) and breast cancer specific survival (BCSS) in patients stratified by 70-gene signature result (high, low, ultralow), and within the ultralow risk group stratified by clinical risk. For these exploratory analyses, we used Kaplan-Meier estimates for time to event endpoints and Cox-regression models to calculate hazard ratio’s (HR). Results: Median follow-up was 8.7 years. Among the ultralow risk patients (n = 1,000), 67% were ≥50 years, 81% had tumors &lt; 2cm, 80% were lymph node negative, 96% had grade 1 or 2 tumors and 99% were ER-positive. Systemic therapy was received by 83% of patients (69% endocrine therapy (ET), 14% ET + CT) and 16% received no adjuvant systemic treatment (AST). Survival estimates for all endpoints are shown in the table; 8-year DMFI was 97.0% (95% CI 95.8-98.1) for ultralow risk. The 8-year DMFI in ultralow risk patients who received no AST or ET only was 97.8% (95% CI 95.3-100) and 97.4% (95% CI 96.1-98.7), respectively. The HR for DMFI was 0.66 (95% CI 0.46-0.95) for ultralow vs low risk, after adjusting for tumor and treatment characteristics (preliminary results). Conclusions: In this prospective study, patients with an ultralow risk 70-gene signature have an excellent prognosis with 8-year BCSS above 99% regardless of clinical risk status, and with an 8-year DMFI of 95-98%.[Table: see text]

Inflammatory cytokines and distant recurrence in HER2-negative early breast cancer in the ECOG-ACRIN 5103 trial.

520 Background: Systemic inflammation may contribute to cancer progression (PMC2803035), including recurrence of early breast cancer (PMC4828958). We hypothesized that inflammatory cytokines and/or chemokines may be associated with distant recurrence (DR). Methods: We performed a case:control study in women with stage II-III Her2-negative breast cancer, all of whom had surgery and adjuvant chemotherapy (doxorubicin/cyclophosphamide, then weekly paclitaxel) with/without bevacizumab, plus endocrine therapy if ER-positive (PMC6118403). Propensity score matching was used to identify approximately 250 case:control pairs (with/without DR). Serum samples obtained before adjuvant chemotherapy were analyzed using the MSD V-Plex Human Cytokine 36-Plex Kit for detection of human cytokines and chemokines involved in the Th1/Th2 pathway, chemotaxis, the Th17 pathway, angiogenesis, and immune system regulation. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations. Due to skewed nature of cytokines, HRs are reported on log base 2 scale. If adjusted for multiple testing including 36 markers, a p value of &lt; 0.0014 would be required for statistical significance. Results: A total 249 matched pairs (498 patients) were identified. Covariates used for propensity score matching included age, menopausal status (post 54% vs. pre/peri 46%), ER/PR status (one/both pos 64% vs. both neg 36%) tumor size ( &lt; = 2cm 17%, &gt; 2-5cm 67%, &gt; 5cm 16%) nodal status (neg 15%,1-3+ 32%, 4+ 53%), and grade (low 3%, int. 31%, high 66%). The only biomarker associated with a significantly increased DR risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Others associated with a 2-sided p value &lt; 0.05 included the chemokine MDC(macrophage-derived chemokine/CCL22) (1.90, 95% CI 1.17, 3.1, p = 0.0098), the T helper cell inflammatory cytokine IL-17A (HR 1.36, 95% CI 1.10, 1.67, p = 0.0052), and the cytokine VEGF-A (HR 1.13 for, 95% CI 1.01, 1.27, p = 0.037). There was no statistical interaction between VEGF-A and bevacizumab benefit. The median and mean value for IL-6 was 0.95 and 7.5 pg/ml (range 0.04-2761.24 pg/ml). Conclusions: This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher DR risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy. This provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway. Supported by NCI U10CA180820,180794,180821; UG1CA189859,232760,233290, 233196; Komen Foundation; Breast Cancer Research Foundation. Clinical trial information: NCT00433511.

S1801: A randomized trial of adjuvant versus neoadjuvant pembrolizumab for melanoma.

TPS9585 Background: Although long term outcomes for most patients with early-stage melanoma is excellent following surgery, patients who have high-risk features such as lymph node involvement have poorer outcomes. Adjuvant therapy (AT) is currently considered for patients with stage III melanoma and selected patients with resected stage IV melanoma. Currently, AT for melanoma is anti-PD-1 or targeted therapy in the presence of a BRAF mutation. At this time, we are not able to predict which patients will derive benefit from AT and experience cure. While curative intent is the goal of treatment for primary melanoma, patients with bulky nodal involvement are at high risk of local or distant recurrence despite upfront surgery. Neoadjuvant treatment (NAT) offers the benefit of an early on-treatment pathological sample that can be profiled for biomarkers and correlated with response and survival. Treating with anti-PD1 while tumor remains visible in the body may generate a stronger immune response against in vivo tumor antigens compared to the traditional adjuvant setting where antigen is presented by microscopic residual tumor burden. Pilot studies of NAT with anti-PD-1 therapy have been initiated in melanoma. Multidisciplinary coordination in these cases is paramount. In these studies, an improvement in relapse-free survival and overall survival has been observed; additionally, pathologic response rates to NAT have been estimated in small studies. Methods: S1801 is a randomized phase II study of AT versus NAT with pembrolizumab (PEM, NCT03698019). Patients with measurable, clinically detectable and resectable cutaneous, acral, and mucosal melanomas without brain metastasis are eligible. Patients with Stage IIIB to oligometastatic, resectable Stage IV are randomized 1:1 to AT or NAT. Patients getting AT undergo surgery first followed by 18 doses of PEM 200 mg IV every 3 weeks. Patients getting NAT receive 3 doses of pre-operative PEM followed by surgery and then 15 doses of adjuvant PEM. Radiation may be given on either arm after surgery, at the investigator’s discretion. Primary endpoint is event-free survival measured from the date of randomization to the date of first documented progression that renders the patient unable to receive planned protocol surgery, failure to begin adjuvant therapy within 84 days of surgery, relapse after surgery, or death due to any cause. Secondary endpoints include RECIST and iRECIST response rates, as well as a number of surgical outcomes. Safety monitoring is conducted with disease progression and toxicity thresholds. The key Translational Medicine objective of this trial is to determine the pathologic response rate to NAT after 3 doses of PEM. Surgical pathology grossing instructions to ensure readout for pathologic response are provided in the form of training slides. Enrollment is at 40% of a planned 500 patients. Clinical trial information: NCT03698019.

Recurrence and disease-specific survival after 10-year disease-free interval in patients with primary retroperitoneal liposarcoma: Implications for long-term surveillance.

11546 Background: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) following surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined as the long-term natural history of RP-LPS after treatment is poorly understood. We evaluate a cohort of RP-LPS patients—without evidence of disease 10 years following initial resection—to assess the long-term risk of recurrence and disease-specific survival (DSS). Methods: The prospectively maintained UCLA Sarcoma Database was used to identify RP-LPS patients who demonstrated 10-year progression-free survival (10yr-PFS) after initial diagnosis and treatment. Patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. Time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. Results: From 1972-2010, 76 patients with RP-LPS had at least 10 years of follow-up. Of these, 37 (49%) demonstrated 10yr-PFS. Median follow-up was 15 years (range 10-35 years). Among the 10yr-PFS patients, 43% (16/37) developed a recurrence &gt;10 years after the initial surgery, and 19% (7/37) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or peri-operative treatment with radiation or chemotherapy (Table). Conclusions: Patients with primary RP-LPS treated with surgical resection +/- multimodality therapy have a long-term risk of recurrence and disease-specific death that is unacknowledged by current surveillance imaging guidelines. Among the patients with a 10yr-PFS, 43% developed a recurrence and 19% died of disease. These findings suggest a need for lifelong surveillance imaging in patients with RP-LPS.[Table: see text]

Clinical validation of EndoPredict in premenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer.

537 Background: The EndoPredict 12-gene prognostic assay is validated to predict distant recurrence-free survival (DRFS) and response to chemotherapy in post-menopausal women with ER+, HER2- breast cancer. This study evaluated the performance of EndoPredict in pre-menopausal women. Methods: Stored tumor samples from women with ER+, HER2- primary breast cancer who were pre-menopausal at the time of diagnosis and were systemically treated with endocrine therapy alone were obtained from two sites (University of Nottingham and University of Cyprus). These samples were tested with EndoPredict to produce a 12-gene molecular score (EP). Pathologic tumor size and nodal status were algorithmically combined with the EP score to produce the clinicomolecular EPclin score. Cases with tumors &gt; pT3, which were treated with chemotherapy, or for whom the EPclin score was missing or invalid were excluded. Associations of EP and EPclin with 10-year DRFS were evaluated in terms of hazard ratios (HRs) from Cox proportional hazards models stratified by cohort. 10-year DRFS was estimated for EPclin high-risk and low-risk women by Kaplan-Meier analysis. Results: Out of 411 eligible cases, 385 had a valid EPclin score and were included in the analysis. Mean age at breast cancer diagnosis was 46.5 years (standard deviation 4.7). Most women (N = 239, 62.6%) had grade II tumors and 16.1% (N = 62) had node-positive disease. Over the observation period (median 9.7 years, interquartile range 6.6-13.9 years), 35 women had a distant recurrence within 10 years. Both the molecular EP score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence [HR 1.3, 95% confidence interval (CI) 1.2-1.5; p &lt; 0.001 and HR 3.6, 95% CI 2.3-5.7; p &lt; 0.001, respectively]. Of these patients, 249 (64.7%) were categorized as low risk by EPclin score while the remaining 136 (35.3%) were categorized as high risk. Compared to EPclin low-risk women, EPclin high-risk patients were more likely to experience distant recurrence (HR 4.6, 95% CI 1.4-15.2; p = 0.004). At 10 years post-diagnosis, EPclin low-risk women who received endocrine therapy alone had a DRFS of 97% (95% CI 93-99%). Conversely, EPclin high-risk women had a DRFS of only 76% (95% CI 67-82%). Conclusions: The EPclin score is highly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. Based on these data, pre-menopausal women with EPclin low-risk breast cancer may safely forgo adjuvant chemotherapy in addition to endocrine therapy.

Patterns of failure after definitive treatment for T4a larynx cancer in the Veterans Affairs Health System.

e18006 Background: Both chemoradiotherapy (CRT) and total laryngectomy (TL) with adjuvant therapy are curative-intent treatment options for patients with T4a larynx cancer. Disease recurrence is a known negative prognosicator, but differences in recurrence patterns and the subsequent survival associations are not well characterized. To address this knowledge gap, we present long-term recurrence and survival outcomes from a novel longitudinal data source. Methods: Retrospective study of non-metastatic T4a larynx cancer patients diagnosed between 2000-2017 who underwent curative-intent treatment (TL with adjuvant therapy or primary CRT) from the VA Informatics and Computing Infrastructure database. Adjuvant therapy consisted of either postoperative radiotherapy (RT) or CRT. Fine-Gray and Cox models were used to evaluate primary outcomes – time to locoregional recurrence and distant recurrence. Secondary outcomes included overall survival (OS), cancer-specific survival (CSS), non-cancer specific survival (NCSS), and disease-free survival (DFS). These multivariable models accounted for age, race, alcohol history, smoking status, education and income, Charlson-Deyo score, N-classification, and tumor subsite. Results: The study included 1,114 patients with a median follow-up time of 63.3 months among those alive at last follow up. In the TL group, adjuvant RT was used in 69% and adjuvant CRT was used in 31%. Median time to first recurrence was 24.4 months with overall incidence of 28.5% locoregional and 9.5% distant recurrence. Primary CRT patients had higher rates of locoregional (37.2 vs. 22.9%) and distant recurrence (13.3 vs. 7.0%) (p &lt; 0.0001). Median OS was 27.3 months for CRT (95% CI: 23.6-32.4 months) and 47.5 months (95% CI: 39.6-52.1 months) for TL. Median DFS was 14.1 months for CRT (95% CI:12.5-17.2 months) and 37.9 months (95% CI 31.2-47.5 months) for TL. On multivariable analysis compared to CRT, TL was associated with longer time to locoregional (HR 0.50, 95% CI:0.40-0.61) and distant recurrence (HR 0.50, 95% CI:0.34-0.73). Having N+ disease increased risk of distant recurrence (HR 2.20, 95% CI:1.42-3.41). TL was associated with improved OS (HR 0.78, 95% CI:0.67 – 0.91), CSS (HR 0.73, 95% CI:0.59 – 0.89), and DFS (HR 0.58, 95% CI 0.49-0.69) compared to CRT; NCSS was equivalent between groups (HR 1.09, 95% CI:0.88-1.35). Of the CRT patients with locoregional failures, 67/163 (41.1%) were salvaged with surgery. Conclusions: In this cohort of T4a larynx cancer patients, surgical management demonstrated favorable recurrence and survival results. TL with adjuvant therapy was associated with significantly lower incidence of both locoregional and distant recurrence and increased OS, CSS and DFS compared to CRT. Lower probability of disease recurrence, in addition to a survival advantage, should be considered as an important advantage to up-front surgery.

Utility of the 70-gene MammaPrint assay for prediction of benefit from extended letrozole therapy (ELT) in the NRG Oncology/NSABP B-42 trial.

502 Background: The 70-gene MammaPrint (MP) assay predicts risk of distant recurrence (DR) in hormone-receptor positive early-stage breast cancer and classifies cancers as Low Risk or High Risk. NSABP B-42 evaluated ELT in patients (pts) who had completed 5 yrs of adjuvant endocrine therapy (tx). The primary objective was to determine the utility of MP to identify pts enrolled in NSABP B-42 who are likely to benefit from ELT. Methods: A total of 1,866 pts from B-42 had available MP results. Primary endpoint is DR. Secondary endpoints are disease-free survival (DFS) and breast cancer-free interval (BCFI). For the primary analysis, pts were classified as High Risk (MP-H) (MP score ≤0.000) or Low Risk (MP-L) (MP score &gt; 0.000). Exploratory analyses were performed for MP-L subcategories: MP Ultralow Risk (MP-UL) (MP score &gt; 0.355) and MP-L but not MP-UL (MP-LNUL) (MP score &gt; 0.000, ≤0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model was used for treatment by risk group interaction. Stratified log-rank test was used to compare treatment groups. Hazard ratios and 95% CI were computed based on the stratified Cox PH model. Results: Among 1,866 pts, 706 (38%) were MP-H and 1,160 (62%) were MP-L. Of the MP-L, 252 (22%) were MP-UL. There were no significant differences in the distribution of patient and tumor characteristics between the MP group and the rest of the B-42 cohort, except for HER2 status. ELT effect was more pronounced in the MP cohort than in the overall B-42 population. For DR, there was statistically significant ELT benefit in MP-L (HR = 0.43, 95% CI 0.25-0.74, p = 0.002), but not MP-H (HR = 0.65, 0.34-1.24, p = 0.19) (interaction p = 0.38). For DFS, there was statistically significant ELT benefit in MP-L, but not MP-H (interaction p = 0.015). Similar findings were observed for BCFI (interaction p = 0.006). Within subcategories of MP-L, there was statistically significant ELT benefit in MP-LNUL, but not in MP-UL for all three endpoints, however the power in MP-UL was limited due to low number of pts (Table). Clinical trial information: 00382070. Conclusions: Statistically significant ELT benefit was observed for MP-L, but not MP-H. The treatment by risk group interaction was not statistically significant for DR, but it was for DFS and BCFI. The benefit appears to be stronger in MP-LNUL than in MP-UL. NCT: 00382070. Support: U10CA180868, -180822, U24CA196067; Novartis; Agendia.[Table: see text]

A simulation model-based clinical decision tool to guide personalized treatment based on individual characteristics: Does 21-gene recurrence score assay testing change decisions?

e12507 Background: There is a need for web-based decision tools that integrate clinicopathologic features and genomic information to guide breast cancer therapy for women with node-negative, hormone receptor positive, HER2 negative (“early-stage”) breast cancer. We developed a novel simulation model-based clinical decision tool that provides prognostic estimates of treatment outcomes based on age, tumor size, grade, and comorbidities with and without 21-gene recurrence scores (RS). Methods: We adapted an extant breast cancer simulation model developed within the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) to derive estimates for the 10-year risks of distant recurrence, breast cancer-specific mortality, other cause mortality and life-years gained with endocrine vs. chemo-endocrine therapy for individual women based on their age, tumor size, grade, and comorbidity-level with and without RS test results. The model used an empiric Bayesian analytical approach to combine information from clinical trials, registry and claims data to provide individual estimates. External validation of the model was performed by comparing model-based breast cancer mortality rates and observed rates in the Surveillance Epidemiology and End Results (SEER) registry. Results: Several exemplar profiles were selected to illustrate the clinical utility of the decision tool. For example, the absolute chemotherapy benefit for 10-year distant recurrence risk and life-years gained, without RS testing, and the outcomes if a woman got tested and had a RS 16-20 are provided below for a 40-44-year-old woman and a 65–69-year-old woman diagnosed with a small (≤2cm), intermediate grade tumor and mild comorbidities. Conclusions: Simulation modeling is useful for creating clinical decision tools to support shared decision making for early-stage breast cancer treatment.[Table: see text]

Application of RSClin to guide treatment recommendations for premenopausal patients with early-stage hormone-positive breast cancer and intermediate risk oncotype recurrence scores.

e12511 Background: The RSClin model, which incorporates the Oncotype Recurrence Score (RS) and clinicopathologic features, was recently developed to further tailor prognosis and prediction of chemotherapy benefit for patients with early-stage hormone positive (HR+) breast cancer (BC) (Sparano et al, 2020). The RSClin calculator is available online to assist treatment planning for situations where chemotherapy benefit is uncertain. Covariates include Oncotype RS, tumor grade, tumor size and patient age. The risk calculator generates a 10-year distant recurrence risk and absolute chemotherapy benefit. This tool may be especially helpful to determine treatment management for premenopausal patients with early-stage HR+ BC with intermediate risk (IR) Oncotype RS (16-25). We retrospectively applied RSClin to this patient population to determine if it would have changed treatment recommendations. Methods: We identified premenopausal women with node-negative early-stage BC with IR RS (16-25) within our large Oncotype database. Using the RSClin model, we selected &gt;5% absolute chemotherapy benefit as a reasonable cutoff to recommend chemotherapy. We compared the treatment recommendation based on RSClin with the treatment previously recommended by breast oncologists at our large academic medical center in New York City. Results: There were 86 patients who met criteria with a median age of 46 years. Of these, 26 patients (30%) were recommended chemotherapy plus endocrine therapy (ET) and 60 (70%) were recommended ET alone. After applying the RSClin model (data available for 83/86 patients), 19 (23%) would have resulted in a change in treatment recommendation and 64 (77%) would have remained unchanged. Overall, 8 (10%) would have withheld chemotherapy when it was previously offered and 11 (13%) would have recommended chemotherapy when it was previously excluded. There were 8 (9%) secondary invasive breast events in this population, with 2 (2%) being ipsilateral, 3 (3%) being contralateral and 3 (3%) metastatic at a median follow up of 46.9 months. Conclusions: The RSClin model would have changed management of premenopausal patients with IR RS in 23% of patients. This model, although not yet prospectively validated, may help individualize therapy for patients with less definitive treatment plans. Using RSClin, we can aim to minimize recurrence rates and avoid unnecessary chemotherapy in selected patients. This model is easy to apply and will have important clinical utility moving forward.

Predicting Adverse Pathologic Features and Clinical Outcomes of Resectable Pancreas Cancer With Preoperative CA 19-9.

BackgroundWe evaluated preoperative CA 19-9 levels in patients with resected pancreatic cancer to analyze whether they were predictive of clinical outcomes and could help select patients for additional therapy. We hypothesized that elevated CA 19-9 would be associated with worse pathologic findings and oncologic outcomes.MethodsThis study assessed 509 patients with non-metastatic pancreatic adenocarcinoma who underwent resection at our institution from 1995-2011 and had preoperative CA 19-9 recorded. No patients received neoadjuvant therapy. CA 19-9 level was analyzed as a continuous and a dichotomized (> vs. ≤ 55 U/mL) variable using logistic and Cox models.ResultsMedian follow-up was 7.8 years, and the median age was 66 years (33-90). 64% of patients had elevated preoperative CA 19-9 (median: 141 U/mL), that did not correlate with bilirubin level or tumor size. Most patients had ≥ T3 tumors (72%) and positive lymph nodes (62%). The rate of incomplete (R1 or R2) resection was 19%. Increasing preoperative CA 19-9 was associated with extra-pancreatic extension (p=0.0005), lymphovascular space invasion (p=0.0072), incomplete resection [HR (95% CI) 2.0 (1.2-3.5)], and lower OS [HR = 1.6 (1.3-2.0)]. Each doubling in preoperative CA 19-9 value was associated with an 8.3% increased risk of death [HR = 1.08 (1.02-1.15)] and a 10.0% increased risk of distant recurrence [HR = 1.10 (1.02-1.19)]. Patients classified as non-secretors had comparable outcomes to patients with normal CA 19-9.ConclusionsElevated preoperative CA 19-9 level was associated with adverse pathologic features, incomplete resection, and inferior clinical outcomes. Neither tumor size nor bilirubin confound an elevated CA 19-9 level. Preoperative CA 19-9 level may help select patients for additional therapy.

Evaluation of the ability of the Clinical Treatment Score at 5\xa0years (CTS5) compared to other risk stratification methods to predict the response to an extended endocrine therapy in breast cancer patients

PurposeExtension of adjuvant endocrine therapy (ET) reduces the risk of recurrence in women diagnosed with ER-positive breast cancers, but a significant benefit is unlikely to happen to all individual patients. This study is aimed at evaluating the ability of different clinical late distant recurrence (LDR) risk stratification methods and in particular the clinical treatment score at 5 years (CTS5) to predict the response to extended adjuvant ET.Methods783 patients diagnosed with ER+ BC between 1988 and 2014 at Umberto I Hospital of Turin, of which 180 received an extended adjuvant ET, were retrospectively selected. They were stratified according to pT, pN, disease stage, tumor grade, Ki67 level, progesterone receptor status and CTS5. The primary endpoint was LDR rate. LDR rates according to ET duration were confronted in each subgroup.ResultThe median duration of extended ET was 7 years (6–10). Median follow-up from diagnosis was 9 years (6–26). Retrospective risk stratification according to tumor size, nodal status, disease stage, tumor grade, Ki67 level, and progesterone receptor status did not appear to be able to predict the response to extended ET. In the CTS5 high-risk subgroup instead, the risk of developing an LDR was significantly lower in the patients who underwent extended ET compared to standard ET (HR 0.37, 95% CI 0.15–0.91), while no significant benefit was demonstrated for low and intermediate-risk patients.ConclusionsRisk stratification according to CTS5 appeared to be predictive of the response to extended endocrine therapy in our population of real-life pre and postmenopausal patients.

Leiomiosarcoma pleomórfico renal primario: Reporte de caso y revisión de la literatura

Introduction: Renal leiomyosarcoma is a rare disease, it constitutes 0,12% of malignant renal tumors, the renal mass is identified by imaging studies, but the diagnosis is given by histopathology and immunohistochemistry. The standard treatment is radical nephrectomy and the role of chemotherapy and radiotherapy is not yet well defined. Objective: To provide updated information on the diagnosis and treatment of primary renal pleomorphic leiomyosarcoma. Materials and methods: Case report and bibliographic review study of 10 scientific articles found in the Medline, Scielo and PubMed databases. The search criteria used consisted of terms: Renal leiomyosarcoma, mesenchymatous tumor, renal tumor Case report: 34-year-old patient with low back pain, which in imaging studies shows a left renal mass, a radical nephrectomy is performed. The histopathological study reported pleomorphic renal leiomyosarcoma. Results: Simple and contrasted uro-tomography is the specific diagnostic method for the detection of renal masses; histopathology and immunohistochemistry provide information on the tumor lineage. Conclusions: Renal leiomyosarcoma is a rare and aggressive renal tumor, its first-line treatment is radical nephrectomy; it is a tumor with a high risk of local and distant recurrence, it is considered a chemo-sensitive tumor, thus chemotherapy is considered an optional therapy.

356 Polypoid melanoma is associated with aggressive histopathological characteristics and poor clinical prognosis

Polypoid melanoma is a rare subtype of melanoma characterized by pedunculated exophytic growth. These tumors tend to have a thick Breslow depth, but it is unknown if the prognosis of this subtype is worse compared to other variants of melanoma. A retrospective review was performed of 37 polypoid melanomas and compared to 264 non-polypoid nodular melanomas. Each case was independently re-evaluated by board-certified dermatopathologists for the following histopathologic parameters including Breslow depth, mitotic rate, ulceration, and angiolymphatic invasion. Basic demographic data and clinical characteristics were collected from electronic medical record data and compared, including clinical stage at diagnosis, rates of recurrence, and survival, between polypoid and nodular melanoma subtypes. Patients with polypoid melanoma had a younger average age than patients with nodular melanoma. Histopathologic review revealed that polypoid tumors had a significantly higher average Breslow depth, and had a higher frequency of ulceration and angiolymphatic invasion than nodular melanomas. Analysis of clinical outcomes by log-rank test showed a higher risk of distant recurrence and worse overall survival in polypoid tumors compared to nodular melanomas. Multivariate analysis showed an association of polypoid subtype with higher distant recurrence and worse survival. This association was independent of other prognostic factors including Breslow depth and ulceration. This study shows that polypoid melanoma is associated with a higher frequency of aggressive histopathological characteristics and poor clinical prognosis compared to non-polypoid nodular melanoma.

Serum carcinoembryonic antigen pre-operative level in colorectal cancer: revisiting risk stratification.

Biomarkers may play a role as predictive and prognostic factors in colorectal cancer patients. The aims of the study were to verify the prognostic role of pre-operative serum carcinoembryonic antigen (CEA) level in predicting overall survival and risk of recurrence in a cohort of colorectal cancer patients and to evaluate optimal cut-off values. A retrospective cohort analysis was performed on colorectal cancer patients undergoing elective curative surgery between 2004 and 2019 at an Italian Academic Hospital. Main outcomes were overall survival, disease-free survival at 3-years and risk of local, loco-regional and distant recurrence during follow-up. A receiver operating characteristic (ROC) curve analysis was plotted using CEA pre-operative values and follow-up data in order to estimate the optimal cut-off values. A total of 559 patients were considered. The mean CEA value was 12.1 ± 54.1ng/mL, and the median 29.3 (0-4995) ng/mL. The ROC curve analysis identified 12.5ng/mL as the best CEA cut-off value to predict the risk of metastatic development after surgery in stage I-III colorectal cancer patients, and 10ng/mL as the best CEA cut-off value to predict overall survival and disease-free survival in stage III-IV patients. These data suggest a stratification of colorectal cancer patients in three classes of risk: a low risk class (CEA <10 ng/mL), a moderate risk class (CEA 10-12.5 ng/mL) and a high risk class (CEA >12.5 ng/mL). In conclusion, pre-operative serum CEA measurements could integrate information to enhance patient risk stratification and tailored therapy.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial

Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences. We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 intravenously every 14 days for 6 cycles), chemoradiotherapy (50 Gy during 5 weeks and 800 mg/m2 concurrent oral capecitabine twice daily for 5 days per week), total mesorectal excision, and adjuvant chemotherapy (3 months of modified FOLFOX6 [intravenous oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2, followed by intravenous 400 mg/m2 fluorouracil bolus and then continuous infusion at a dose of 2400 mg/m2 over 46 h every 14 days for six cycles] or capecitabine [1250 mg/m2 orally twice daily on days 1-14 every 21 days]). The standard-of-care group received chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy (for 6 months). The primary endpoint was disease-free survival assessed in the intention-to-treat population at 3 years. Safety analyses were done on treated patients. This trial was registered with EudraCT (2011-004406-25) and ClinicalTrials.gov (NCT01804790) and is now complete. Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction). Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice. Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Exploring the effects of genomic testing on fear of cancer recurrence among breast cancer survivors.

Fear of cancer recurrence (FCR) is the greatest unmet psychosocial need among breast cancer survivors (BCS). The Oncotype Dx® test predicts the 10-year risk of distant recurrence and benefit of adjuvant chemotherapy among women with early stage hormone receptor-positive breast cancer. Despite the test's clinical utility, psychosocial responses are poorly understood. A descriptive cross-sectional study was conducted to explore associations between Oncotype Dx® test results (Recurrence Score [RS]) and FCR, health-related quality of life (HRQOL), distress, anxiety, depression, illness representation and perceived risk. Bivariate analyses were used to examine the associations between variables followed by multiple linear regression to examine predictors of FCR. Greater FCR was associated with higher distress, anxiety, depression, illness representation and poorer HRQOL. BCS's with a high Oncotype Dx® RS reported higher overall fear (p=0.013) and greater perceived consequences of their cancer (p=0.034) compared to BCS's with a low RS. Using multiple linear regression, anxiety ( =0.21, p=0.016), greater emotional response =0.45, p<0.001) and perceived consequences ( =0.18, p=0.039) of illness explained 58% of the variance (p<0.001) in FCR. BCS's with higher risk of recurrence may experience higher FCR. However, for FCR, modifiable factors such as anxiety and illness representation (greater emotional response and perceived consequences of illness) may be more important than non-modifiable factors such as Oncotype Dx® test results and age. Further research is needed to develop personalized interventions to improve BCS's outcomes.

AB002. SOH21AS038. Optimal timing of surgery following breast cancer neoadjuvant chemotherapy: a systematic review and meta-analysis

Background: The indications for neoadjuvant breast cancer treatment have expanded rapidly in recent decades. Administration of chemotherapy before surgery has the potential to reduce the risk of distant recurrence by targeting circulating micrometastases as well as allowing a more minimalistic approach to surgical intervention. This study aimed to determine the optimum timing of surgery post breast cancer neoadjuvant chemotherapy (NACT).

Clinical Impact of Presurgery Circulating Tumor DNA after Total Neoadjuvant Treatment in Locally Advanced Rectal Cancer: A Biomarker Study from the GEMCAD 1402 Trial

Abstract Purpose: Total neoadjuvant treatment (TNT) is a valid strategy for patients with high-risk locally advanced rectal cancer (LARC). Biomarkers of response to TNT are an unmet clinical need. We aimed to determine the value of circulating tumor DNA (ctDNA) to predict tumor response, recurrence, and survival in patients with LARC treated with TNT. Experimental Design: The GEMCAD 1402 was a phase II randomized, multicentric clinical trial that randomized 180 patients with LARC to modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) +/− aflibercept, followed by chemoradiation and surgery. Plasma samples were collected at baseline and after TNT within 48 hours before surgery (presurgery). An ultrasensitive assay that integrates genomic and epigenomic cancer signatures was used to assess ctDNA status. ctDNA results were correlated with variables of local tumor response in the surgery sample, local/systemic recurrence, and survival. Results: A total of 144 paired plasma samples from 72 patients were included. ctDNA was detectable in 83% of patients at baseline and in 15% following TNT (presurgery). No association was found between ctDNA status and pathologic response. Detectable presurgery ctDNA was significantly associated with systemic recurrence, shorter disease-free survival (HR, 4; P = 0.033), and shorter overall survival (HR, 23; P &amp;lt; 0.0001). Conclusions: In patients with LARC treated with TNT, presurgery ctDNA detected minimal metastatic disease identifying patients at high risk of distant recurrence and death. This study sets the basis for prospective clinical trials that use liquid biopsy to personalize the therapeutic approach following TNT.

IP6K2 predicts favorable clinical outcome of primary breast cancer.

The inositol hexakisphosphate kinase (IP6K) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53. A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be.