High Risk Of Disease Recurrence Research Articles

Potential Clinical Utility of a Targeted Circulating Tumor DNA Assay in Esophageal Adenocarcinoma.

Objective:To explore the clinical utility of circulating tumor DNA (ctDNA) in esophageal adenocarcinoma (EAC) by developing a cost-effective and rapid technique utilising targeted amplicon sequencing.Summary of background data:Emerging evidence suggests that levels of ctDNA in the blood can be used to monitor treatment response and in the detection of disease recurrence in various cancer types. Current staging modalities for EAC such as computerised tomography of the chest/abdomen/pelvis (CT) and positron emission tomography (PET) do not reliably detect occult micro-metastatic disease, the presence of which signifies a poor prognosis. After curative-intent treatment, some patients are still at high risk of recurrent disease, and there is no widely accepted optimal surveillance tool for patients with EAC.Methods:Sixty-two patients with EAC were investigated for the presence of ctDNA using a tumor-informed approach. We designed a custom targeted amplicon sequencing panel of target specific primers covering mutational foci in 9 of the most commonly mutated genes in EAC. Serial blood samples were taken before and after neoadjuvant treatment (NAT), and during surveillance.Results:Somatic mutations were detected in pre-treatment biopsy samples of 55 out of 62 (89%) EAC patients. Mutations in TP53 (80%) were the most common. Out of these 55 patients, 20 (36%) had detectable ctDNA at baseline. The majority (90%) of patients with detectable ctDNA had either locally advanced tumors, nodal involvement or metastatic disease. In patients with locally advanced tumors, disease free survival (DFS) was more accurately stratified using pre-treatment ctDNA status [HR 4.34 (95% CI 0.93–20.21); P = 0.05] compared to nodal status on PET-CT. In an exploratory subgroup analysis, patients who are node negative but ctDNA positive have inferior DFS [HR 11.71 (95% CI 1.16-118.80) P = 0.04]. In blood samples taken before and following NAT, clearance of ctDNA after NAT was associated with a favourable response to treatment. Furthermore, patients who are ctDNA positive during post-treatment surveillance are at high risk of relapse.Conclusions:Our study shows that ctDNA has potential to provide additional prognostication over conventional staging investigation such as CT and PET. It may also have clinical utility in the assessment of response to NAT and as a biomarker for the surveillance of recurrent disease.

Development and validation of nomograms for predicting survival and recurrence in patients with parotid gland cancer.

To develop nomograms for predicting recurrence risk and long-term survival in patients with parotid gland cancer (PGC). A total of 301 consecutive patients with PGC who underwent surgery were enrolled and randomly divided into a training cohort (n=210) and a validation cohort (n=91). Predictive nomograms were constructed based on the independent indicators of overall survival (OS) and disease-free survival (DFS) as determined by multivariate Cox regression analysis. The discrimination and calibration of nomograms were evaluated using C-indices and calibration curves. Six independent predictors of OS were identified. Incorporating these factors, the nomogram showed good concordance statistics of 0.84 and 0.78 in predicting the 5-year OS in the training and validation cohorts. Five independent predictors of DFS were identified and integrated into the nomogram. The concordance statistics were 0.84 and 0.74 in predicting the 5-year DFS in the training and validation cohorts. The predictive performance of the nomograms outperformed the TNM model. Additionally, the patients were divided into two groups according to the nomogram score, and significant differences in OS and DFS were observed between the high risk and low risk groups. Finally, the role of postoperative treatments was evaluated based on the risk stratification; patients at high risk of disease recurrence showed an improvement in DFS after receiving postoperative treatments. The nomogram showed good performance in predicting both OS and DFS in patients with PGC. It might be useful for selecting patients for postoperative treatments.

Optimal Management for Residual Disease Following Neoadjuvant Systemic Therapy.

Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.

Bone Health Outcomes from the International, Multicenter, Randomized, Phase3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer.

IntroductionD-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting.MethodsThe study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated.ResultsOverall, 4509 women with early-stage breast cancer were assigned to receive denosumab (N = 2256) or placebo (N = 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66–1.02; p = 0.068), with HRs of 0.70 (95% CI 0.52–0.94; p = 0.018) for patients < 50 years old and 0.74 (95% CI 0.55–0.98; p = 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63–0.92; p = 0.004) and 0.52 (95% CI 0.35–0.78; p = 0.001), respectively, again favoring the denosumab group.ConclusionThe exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab.Trial Registration NumberNCT01077154

Clinical Implications of TP53 Mutations and p53 Dysfunction in Patients with Myelodysplastic Syndrome (MDS). a Study from the Italian MDS Clinical Network

Introduction. In myelodysplastic syndromes (MDS) TP53 mutations are present in <10% of newly diagnosed patients (pts) and in >30-40% of those with therapy-related MDS. Loss of the TP53 locus represents one of the most powerful risk factors. TP53 mutations frequently result in loss of trans-activating function and stabilization of mutant p53 proteins, leading to their increased accumulation at cellular level (detectable by immunohistochemistry). However, p53 stabilization in cancer can also be observed in the presence of wild-type TP53 alleles, frequently associated with altered expression of p53 regulatory elements (Nat Rev Cancer 2014;14:359-370). In this study we evaluated the prevalence and clinical implications of p53 dysfunction in a large MDS populationMethods. We retrospectively studied a cohort of 998 MDS pts receiving best supportive care (BSC, n= 495), hypomethylating agents (HMAs, n= 198) and allogeneic transplantation (HSCT, n= 305). We used massively parallel sequencing to examine tumor samples somatic mutations in 30 recurrently mutated genes in myeloid neoplasms (JCO 2016;30:3627-3637). To detect p53 protein expression, paraffin sections were stained with DO-1 antibody (Santa Cruz Biotechnology, Santa Cruz, CA),according to a standardized technique (JCO 2011;29:1971-1979). Recursive partitioning was used to generate a hierarchical model for overall survival integrating clinical and genetic characteristics (NEJM 2017;376:536-47)Results. TP53 mutations were detected in 11% of pts. Pts with TP53 mutations of had a paucity of other gene mutations; TP53 mutations were infrequent in pts with splicing mutations vs pts with wt splicing factor genes (P=.002). TP53 mutations were associated to advanced disease according to R-IPSS (P=.02) and poor/very poor cytogenetic risk (P<.001). Survival of pts with TP53 mutation was shorter than wt (15 vs 66 months, P < .001) and it retained significance in multivariable model. None of the sequentially analyzed samples showed a disappearance of the mutant clone or emergence of new clones, suggesting an early occurrence of TP53 mutations. A reduction in mutant clone correlated with response to HMAs and HSCT, however clones increased in non-responders and persisted at disease relapse.In order to define pts with p53 dysfunction, a threshold of 2% of positive cells (p53++/dark brown, nuclear staining) was used, based on the correlation with TP53 mutational status (negative and positive predictive value for the presence of mutation were 96% and 79%, respectively) and the capability to capture an high risk of leukemic evolution. The concordance between the reviewers of bone marrow histology resulted in >95% agreement (P<.001) for recognition of percentage of p53++ cells. Focusing on MDS with increased p53 expression (17% of the whole population), subjects carrying TP53 gene mutations showed a survival comparable to that of pts with wild type TP53 gene (15 vs 17 months, P=ns).We than defined a disease category, i.e. MDS with p53 dysfunction, including pts with TP53 mutations and/or p53 hyperexpression. We did a recursive partitioning analysis considering in addition hematological features and gene mutations as variables. In pts receiving BSC, p53 dysfunction was the most relevant independent prognostic factor associated with increased risk of disease progression and short OS (p=0.001)(Figure 1A). In pts treated with HMAs, p53 dysfunction was associated with lower complete remission rates (21% vs 25%; p=.038) and higher probability of relapse (p=.01). In MDS who received HSCT, the presence of p53 dysfunction was the most important prognostic variable associated with the risk of transplantation failure due to high risk of disease recurrence (p=0.002)(Figure 1B).Conclusions. TP53 mutations occur in about 10% of MDS cases, while wild-type p53 dysfunction due to non-mutational p53 abnormalities appear to be rather frequent in these diseases. MDS with p53 dysfunction appear to be a distinct clinical entity characterized by poor prognosis due to high risk of disease evolution and low probability of response to conventional treatments. TP53 genotyping with evaluation of p53 protein expression may contribute to the precise assessment of p53 status in MDS, thus leading to the identification of cases candidate to a p53-based therapy.Figure 1 OS based on recursive partitioning analysis in A) 495 MDS pts receiving BSC B) 305 pts treated with HSCT [Display omitted] DisclosuresSantini:Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Otsuka: Consultancy; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Santoro:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Novartis, Roche/Genentech, Amgen, Italfarmaco: Consultancy; Novartis, Amgen, Celgene, Sanofi: Other: Travel, Accomodations, Expenses.

Prognostic analysis of patients with T1 stage high grade of bladder urothelial carcinoma and glandular differentiation

Objective: To evaluate the recurrence and progression of patients with pT1 high grade urothelial carcinoma of bladder (UCB) and glandular differentiation. Methods: We retrospectively analyzed the clinical and pathological information of 208 patients diagnosed as pT1 high grade urothelial carcinoma in the Fifth Central Hospital of Tianjin from January 2006 to February 2019.Among them, 78 cases were diagnosed as glandular differentiation (UCGD), the other 130 patients without histologic variants were served as control. The UCGD group included 62 male and 16 female, whose median age was 67 years old (range 38-81 years old). The control group contained 105 male and 25 female, whose median age was 66 years old (range 40-82 years old). Kaplan-Meier and Cox proportional hazard regression analyses were used to evaluate the predictors of oncologic outcomes. Results: The disease recurrence rate and progression rate in UCGD group were 65.4% (51/78) and 28.2% (22/78), higher than 38.5%(50/130) and 14.6%(19/130) of control group (P<0.05). The median recurrence time in UCGD group was 41 months while 55 months in the control group. The median progression time in UCGD group was 39 months while 54 months in the control group. According to the univariate analysis, largest tumor size (P=0.030), UCGD (P=0.003) and lymphovascular invasion (LVI) (P=0.032) were associated with disease recurrence. UCGD (P=0.036) and LVI (P=0.011) were associated with progression. Additionally, Cox multivariate analysis revealed that UCGD (P=0.001), LVI (P=0.038) were the independent factors of disease recurrence. UCGD (P=0.007) and LVI (P=0.037) were also found to be the independent factors of disease progression. Conclusions: Patients with T1 stage UCB and UCGD are at higher risk of disease recurrence and progression. Therefore, these patients should be followed up closely after being diagnosed and undergo individual treatment according to the situation.

Alpha Interferon in Lymphoproliferative Disorders after Autologous Bone Marrow Transplantation (ABMT).

Background: It has been known since the early 1930s that cells infected with viruses are capable of protecting other cells from viral infection. Isaacs and Lindenmann discovered the protein that partially explained this phenomenon and named it interferon (IFN). Within a few years, the antiproliferative and immunomodulatory cellular effects of this molecule had been identified. Minimal residual disease (MRD) is the main cause of relapse and death, after autologous bone marrow transplantation (ABMT).Aim: to study the efficacy and safety of IFN-α as maintenance therapy after ABMT in patients with chronic lymphoproliferative disorders.Methods: 80 patients treated by ABMT were evaluated; 32 non Hodgkin lymphoma, 30 Hodgkin's disease & 12 multiple myeloma. Gender: 39 men and 41 women. Age from 18 to 60 years old (media 45). On the day 90 after ABMT, they started receiving IFN-α (Roferon-A®) 3 MU, subcutaneously, three times a week, during 12 to 18 months (media 14 months). The historical control population (CP) was selected from the international literature, on patients of the same age group and sex distribution, not receiving IFN-α after ABMT (Horning SJ. Cancer 1985; 56:1305–1310: Hodgkin's disease - Rohatiner AZS. Br J Cancer 1987; 55:225–226 - Osteborg A. Eur J Haematol 1990; 45:153–157).Results: no patient's dead ocurred as a consequence of IFN-α treatment. 80% of side effects in patients receiving interferon were acute. The majority of them are constitutional. They include fatigue, fever, chills, myalgias, headache and anorexia (flu-like syndrome). The appearance of tachyphylaxis depends on the type of IFN used, the route and schedule of administration. These symptoms are usually controlled with paracetamol 500 mg before and after IFN administration. Administration of IFN during the evening or at bed time has been succesful in minimizing the effects of peack toxicity. The hematologic effects of IFN therapy include leukopenia, anemia and thrombocytopenia. The fatigue associated with IFN therapy is often chronic and may require a dose reduction (5% of our patients). The most frequent neurologic side effects are depression, confusion and mental slowing. Mild proteinuria can be seen (low frequency; 1%). Whole alopecia was not present in this cohort. Overall survival (OS) and disease - free interval survival (DFI-S) was evaluated in each group of patients. Hodgkin's disease OS 89% (75% CP), DFI-S 84% (64% CP); non Hodgkin's lymphomas OS 87% (55% CP), DFI-S 56% (39% CP); multiple myeloma OS 92% (52% CP), DFI-S 66% (33% CP). Log rank test highly significant in favor of the population treated with IFN-a (p<0,001).Conclusions: IFN-α has clearly demonstrated its usefulness inducing prolongation of disease free and overall survival in LPDs after ABMT, This may be accomplished by administration of adjuvant IFN to patients at high risk of recurrent disease after ABMT.

Identifying High-Risk Tumors within AJCC Stage IB-III Melanomas Using a Seven-Marker Immunohistochemical Signature.

Simple SummaryImmunotherapy and targeted therapy are widely accepted for stage III and IV melanoma patients. Clinical investigation of adjuvant therapy in stage II melanoma has already started. Therefore, methods for relapse prediction in lower stage melanoma patients apart from sentinel node biopsies are much needed to guide (neo)adjuvant therapies. Gene scores such as the “DecisionDx-Melanoma” and the “MelaGenix” score can help assist therapy decisions. However, a seven-marker immunohistochemical signature could add valuable feasibility to the biomarker toolbox.Background: We aim to validate a seven-marker immunohistochemical signature, consisting of Bax, Bcl-X, PTEN, COX-2, (loss of) ß-Catenin, (loss of) MTAP and (presence of) CD20, in an independent patient cohort and test clinical feasibility. Methods: We performed staining of the mentioned antibodies in tissue of 88 primary melanomas and calculated a risk score for each patient. Data were correlated with clinical parameters and outcome (recurrence-free, distant metastasis-free and melanoma-specific survival). Results: The seven-marker signature was able to identify high-risk patients within stages IB-III melanoma patients that have a significantly higher risk of disease recurrence, metastasis, and death. In particular, the high sensitivity of relapse prediction (>94%) in sentinel negative patients (stages IB–IIC) was striking (negative predictive value of 100% for melanoma-specific survival and distant metastasis-free survival, and 97.5% for relapse-free survival). For stage III patients (positive nodal status), the negative predictive value was 100% with the seven-marker signature. Conclusions: The seven-marker signature can help to further select high-risk patients in stages IIB-C but also in earlier stages IB–IIA and be a useful tool for therapy decisions in the adjuvant and future neo-adjuvant settings. Stage III patients with measurable lymph node disease classified as high-risk with the seven-marker signature are potential candidates for neoadjuvant immunotherapy.

High-risk HPV positivity is a long-term risk factor for recurrence after cervical excision procedure in women living with HIV.

ObjectiveTo evaluate the risk factors for recurrence of high‐grade disease after cervical excision in women living with HIV (WLWH), with a specific interest in the role of high‐risk (HR‐) HPV positivity.MethodsMulticentric retrospective study conducted on WLWH who underwent cervical excision between January 1987 and June 2017 in six Italian institutions. The rate of high‐grade recurrence was determined. Risk factors for recurrence and HR‐HPV positivity were determined with the Log‐rank test and Cox proportional hazards regression models.ResultsA total of 271 WLWH were included in the final analysis. A high‐grade recurrence was found in 58 (21.4%) patients. Age 41 years or more at inclusion and HR‐HPV positivity during follow up were independently associated with a higher risk of disease recurrence with relative risks of 4.15 (95% confidence interval [CI] 2.01–8.58, P < 0.001) and 5.18 (95% CI 2.12–12.67, P < 0.01), respectively. Age 41 years or more (relative risk 1.75, 95% CI 1.01–3.04, P = 0.047) resulted as a risk factor for HR‐HPV positivity during follow up.ConclusionHR‐HPV positivity is a risk factor for recurrence after cervical excision in WLWH. Women older than 41 years may benefit from a long‐term yearly follow up. Future studies regarding HPV vaccination after treatment in WLWH may be useful, considering the protective role of the higher probability of HPV negativity in vaccinated women.

Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease.

The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). While dyslipidemia, type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis, liver related morbidity and mortality becomes relevant for MAFLD’s progressive form, non-alcoholic steatohepatitis (NASH), and upon development of liver fibrosis. Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting. Bariatric surgery, especially Y-Roux bypass, has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases, but comes at a low but existent risk of surgical complications, reoperations and very rarely, paradoxical progression of NASH. Once end-stage liver disease develops, obese patients benefit from liver transplantation (LT), but may be at increased risk of perioperative infectious complications. After LT, metabolic comorbidities are commonly observed, irrespective of the underlying liver disease, but MAFLD/NASH patients are at even higher risk of disease recurrence. Few studies with low patient numbers evaluated if, and when, bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations. In this review, we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient’s needs in light of their risk profile.

EMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 &amp; 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.

EORTC 1707 VESTIGE: Adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—An open-label randomized controlled phase II study.

TPS4156 Background: Gastroesophageal adenocarcinoma (GEA) patients with metastatic lymph nodes (ypN+) or a microscopically incomplete surgical resection (R1) following neoadjuvant chemotherapy are at high risk of disease recurrence. Current practice is to continue with the same perioperative chemotherapy used prior to surgery, despite these suboptimal outcomes. Adjuvant immunotherapy with nivolumab has shown efficacy in poor risk GEA patients following chemoradiotherapy and surgery in the CheckMate 577 trial, and nivolumab and ipilimumab have demonstrated activity in advanced GEA. We hypothesise that high risk (ypN+ and/or R1) post resection GEA patients who are treated with nivolumab and ipilimumab will have better disease free survival than patients who continue with standard post-operative chemotherapy. Methods: VESTIGE is an ongoing, international, open label randomized phase II study designed to evaluate the efficacy of adjuvant nivolumab plus ipilimumab versus standard post-operative chemotherapy in high risk (ypN+ and/or R1) post resection GEA patients. Eligible patients (n=240) will be randomised 1:1 to receive post-operative adjuvant chemotherapy (identical regimen as pre-operatively) or nivolumab 3mg/kg IV q2w plus ipilimumab 1mg/kg IV q6w x 1 year. Key inclusion criteria include ypN+ and/or R1 status following neoadjuvant chemotherapy plus surgery and an adequate pre-specified surgical resection. The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety, toxicity and quality of life. Since start of recruitment in August 2019, the trial has recruited 85 of 240 patients at 18 sites in the Czech Republic, France, Germany, Israel, Italy, Norway, Poland, Spain, and United Kingdom. The VESTIGE translational research programme includes collection of pre-treatment biopsies, post-chemotherapy resection specimens and serial liquid biopsy on treatment to explore biomarkers predictive of immune checkpoint blockade efficacy. Clinical trial information: NCT03443856.

Impact of recurrence on health-related quality of life in patients at high risk of recurrence after radical surgery for muscle-invasive urothelial carcinoma (MIUC): Results from the phase 3 CheckMate 274 trial.

4540 Background: Patients (pts) undergoing radical surgery for MIUC face a high risk of disease recurrence. Recurrence is associated with worse survival, but its effect on health-related quality of life (HRQoL) is unclear. This post hoc analysis assessed the impact of recurrence on HRQoL using data from the phase 3 CheckMate 274 trial. Methods: Pts who had undergone radical surgery for high-risk MIUC (≤ 120 days previously) were randomized 1:1 to nivolumab 240 mg Q2W or placebo for ≤ 1 year. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D-3L every 4–6 weeks during treatment; 35 and 115 days after the last dose; and every 3 months after that until the end of the study (EQ-5D-3L only). The analysis included pts with a valid HRQoL assessment at baseline and at ≥1 post-baseline visits. Confirmed deterioration in HRQoL was defined as worsening exceeding an a priori points threshold (± 10 for the EORTC QLQ-C30 domains, –7 for the EQ-5D visual analogue scale [VAS]) at ≥ 2 consecutive visits. Recurrence was classified as local only or distant (with or without local recurrence). The effect of recurrence on HRQoL deterioration was assessed by Cox proportional hazards regression with recurrence as a time-dependent covariate. The models controlled for treatment arm and baseline HRQoL score, and were stratified by PD-L1 expression, pathologic nodal status, and use of neoadjuvant cisplatin-based chemotherapy. Results: The analysis included 645 pts for EORTC QLQ-C30, of whom 71 (11%) had local recurrence only and 136 (21%) had distant recurrence during the HRQoL assessment period; and 648 pts for EQ-5D-3L. with recurrence had a significantly higher risk of confirmed deterioration in all HRQoL domains than those without recurrence (see table). However, hazard ratios were consistently greater for distant recurrence than for local recurrence across all HRQoL domains. For local recurrence only, a higher risk of confirmed deterioration in HRQoL compared to no recurrence was observed only for global health status/QoL. Conclusions: Recurrence, particularly distant recurrence, had a significant, negative impact on HRQoL. This suggests that treatment delaying recurrence after radical surgery for high-risk MIUC may prevent or delay HRQoL deterioration in these pts. Clinical trial information: NCT02632409. [Table: see text]

Oncologic Safety of Autologous Fat Grafting after Breast Cancer Surgical Treatment: A Matched Cohort Study.

Autologous fat grafting has been an increasingly popular procedure for remodeling the breast of patients undergoing breast cancer surgery. This study's objective was to investigate whether autologous fat grafting is associated with a higher risk of disease recurrence in the context of late breast reconstruction for patients diagnosed with breast cancer who have undergone either breast-conserving surgery or mastectomy. A retrospective matched cohort study was performed in a single tertiary health care center. Data were collected from 42 patients formerly treated for breast cancer who underwent the first session of autologous fat grafting between August of 2007 and June of 2016. A total of 126 patients with similar features, who did not undergo autologous fat grafting, were individually matched at a 1:3 ratio with the autologous fat grafting group. The primary endpoint was locoregional recurrence. Secondary outcomes were rates of local and distant recurrences, disease-free survival, and overall survival. At a mean follow-up of 65 months after fat grafting, no significant differences were found between the lipofilling and control groups for locoregional recurrence (7.1 percent versus 6.3 percent; p = 0.856), local recurrence (7.1 percent versus 5.6 percent; p = 0.705), distant recurrence (14.3 percent versus 7.9 percent; p = 0.238), disease-free survival (21.4 percent versus 19.0 percent; p = 0.837), and overall survival (14.3 percent versus 7.1 percent; p = 0.181). No evidence of increased risk in any of the survival outcomes was identified. Lipofilling seems to be a safe procedure for breast reconstruction after surgical treatment of breast cancer. Therapeutic, III.

Kidney transplant in patients with atypical hemolytic uremic syndrome in the anti-C5 era: single-center experience with tailored Eculizumab

Patients with atypical hemolytic uremic syndrome (aHUS) have long been considered ineligible for kidney transplantation (KTx) in several centers due to the high risk of disease recurrence, graft loss and life-threatening complications. The availability of Eculizumab (ECU) has now overcome this problem. However, the best approach towards timing, maintenance schedule, the possibility of discontinuation and patient monitoring has not yet been clearly established. This is a single center case series presenting our experience with KTx in aHUS. This study included 26 patients (16 females) with a diagnosis of aHUS, who spent a median of 5.5years on kidney replacement therapy before undergoing KTx. We compared the aHUS relapse rate in three groups of patients who underwent KTx: patients who received no prophylaxis, patients who underwent plasma exchange, those who received Eculizumabprophylaxis. Complement factor H-related disease was by far the most frequent etiology (n = 19 patients). Untreated patients and patients undergoing pre-KTx plasma exchange prophylaxis had a relapse rate of 0.81 (CI 0.30-1.76) and 3.1 (CI 0.64-9.16) events per 10years cumulative observation, respectively, as opposed to 0 events among patients receiving Eculizumabprophylaxis. The time between Eculizumabdoses was tailored based on classic complement pathway activity (target to< 30%). Using this strategy, 12 patients are currently receiving Eculizumab every 28days, 5 every 24-25days, and 3 every 21days. Our experience supports the prophylactic use of Eculizumabin patients with a previous history of aHUS undergoing KTx, especially when complement dysregulation is well documented by molecular biology.

65P Patient follow-up of NEOVATTL study

Sentinel lymph node biopsy has gained attention due to its potential for less invasive management of the axilla and the increasing number of early-stage breast cancer patients treated with neoadjuvant systemic therapy prior to surgery. One-Step Nucleic Acid Amplification (OSNA) assay is an accurate and reliable option for intraoperative molecular analysis of SLN status. NEOVATTL study demonstrates its predictive and prognostic value for non-SLN involvement and disease recurrence in breast cancer patients who had received NST. Therefore, the aim of the study was to show the follow-up of those patients that were recruited in NEOVATTL study and to corroborate the favorable prognosis of the patients with low axillary tumour load. This is a multicentric and retrospective study in which the patients underwent intraoperative SLN biopsy after NST. The data was obtained from a Spanish Sentinel Lymph Node database. TTL was defined as the total sum of CK19 mRNA copies in all positive SLNs. A total of 314 patients were included; 75.0% were cN0 prior to NST. 91.7% received chemotherapy with or without biologic therapy, and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement at a cut-off of 15,000 copies/μL had a negative predictive value of 90.5%. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/μL. TTL >15,000 mRNA copies/μL was predictive of non-SLN involvement and TTL >25,000 mRNA copies/μL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST. Follow up between five to ten years have demonstrated a favourable prognosis of patients with low TTL (<15,000mRNA).

Medullary thyroid cancer outcomes in patients with undetectable versus normalized postoperative calcitonin levels.

Calcitonin (Ct) is a sensitive diagnostic biomarker and one of the most important prognostic factors in medullary thyroid cancer (MTC). This study aimed to evaluate progression-free survival and recurrence rates of MTC associated with undetectable compared with normalized serum Ct levels after surgery. This retrospective observational study included patients operated for MTC at the Digestive and Endocrine Surgery Department of Lyon Sud Hospital Centre between 2000 and 2019. Clinical and pathological factors were correlated with postoperative Ct concentrations. Undetectable and normalized Ct concentrations were defined as below 2 pg/ml and 2-10 pg/ml respectively. Overall, 176 patients were treated for MTC, and 127 were considered biochemically cured after surgery. Of these, 24 and 103 had normalized and undetectable Ct concentrations respectively. Patients with Ct level normalization had a 25 per cent risk of disease recurrence, compared with 3 per cent in patients with undetectable Ct levels after surgery. The presence of metastasis in two or more compartments was predictive of failure to achieve undetectable Ct concentrations after surgery and an increased risk of recurrence. Among patients with biochemically cured MTC, those with undetectable or normalized Ct concentrations after surgery had different risks of recurrence. Simply assessing postoperative Ct normalization can be falsely reassuring, and long-term follow-up is needed. Calcitonin (Ct) is a sensitive diagnostic biomarker and one of the most important prognostic factors for medullary thyroid cancer outcomes; however, the significance of postoperative Ct levels remains controversial. This study evaluated the differences between normal and undetectable postoperative Ct levels in patients who had undergone surgical treatment for medullary thyroid cancer. Patients who experienced postoperative Ct level normalization had a higher risk of disease recurrence than those with undetectable Ct levels after surgery.

Prognostic factors for incomplete response in thyroid microcarcinoma: an analysis of initial response to therapy in 517 patients.

Although thyroid microcarcinoma (TMC) usually has a favorable prognosis, some patients present a higher risk of disease recurrence or persistence. Thus, we aimed at identifying possible risk factors associated with an incomplete response to therapy in TMC. This was a retrospective study of 517 patients with TMC treated with total thyroidectomy, with or without radioactive iodine (RAI) therapy, reclassified after 1.1 ± 0.4 years according to the response to treatment into "favourable" (excellent/indeterminate) or "unfavorable" (biochemical/structural incomplete) responses. We evaluated participants' age, sex, tumor size, histological variants, multifocality, presence of vascular/lymphatic/perineural invasion, extrathyroidal extension, metastatic lymph nodes (LN), and distant metastasis. The effect of RAI therapy on the response range was analyzed in a given subgroup. The mean age observed was 46.4 ± 12.0 years, and 89.7% were female. We noted 97.5% with papillary carcinoma, 27.8% with multifocality and 11.2% with LN metastasis. Although the majority of patients had a low risk of recurrence/persistence (78%), 75% were submitted to RAI therapy. Incomplete response (20.7%) was associated with multifocality (p=0.041; OR=1.619) and metastatic LN (p=0.041; OR=1.868). These variables were strongly correlated (p=0.000; OR=3.283). No cut-off of tumor size was identified as a predictor of incomplete response by the receiver operating curve analysis. RAI treatment did not influence the response of patients with multifocality or LN metastasis. Multifocality and LN metastasis are independent risk factors for incomplete response in TMC patients and are strongly correlated. Additional RAI therapy was not associated with a more favorable response in these subgroups.

Abstract PD14-09: Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC)

Abstract Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [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 PD14-09.

Abstract PS18-07: Association between pathological response and tumor genomic profiling in triple negative breast cancer patients treated with neoadjuvant chemotherapy

Abstract Background: Triple negative breast cancer (TNBC) has a marked molecular diversity that promotes clinical heterogeneity. Less than 40% of TNBC patients will achieve a pathological complete response (pCR) to standard neoadjuvant chemotherapy. Patients who do not achieve pCR have a high risk of disease recurrence and subsequent death from breast cancer. Molecular characterization may identify TNBC patients unlikely to achieve pCR and subsequently develop recurrent disease. Methods: We are conducting a multicenter prospective study of clinical stages II and III TNBC patients treated with neoadjuvant docetaxel and carboplatin. We performed tumor whole exome sequencing on 56 patients pre-treatment samples to identify somatic mutation associated with pCR. Thirteen matching samples from cycle 1 day 3 (C1D3) were also analyzed to assess changes in somatic mutation profiles. Results: In this biomarker study, thirty-seven (66.1%) patients are Caucasians, 17 (30.4%) African American. Nineteen (33.9%) achieved pCR following six cycles of neoadjuvant docetaxel and carboplatin. 9063 variants were detected in 5386 unique genes. The overall mutation burden for patients who achieved pCR was not significantly different from non-pCR patients (median of 80 variants, IQR 51-135 in pCR, vs median 72, IQR 44-102 in non-pCR, Wilcoxon rank sum test p=0.78). As expected, TP53 is the most frequently mutated gene observed in 48 of all 56 patients (85.7%). There was a non-significant trend with lower TP53 mutations occurring in 78.9% of patients with pCR, versus 89.2% of non-pCR patients (OR 0.46, 95% CI 0.07 - 2.83; p value 0.42). BRCA2 somatic mutations were observed in 5.4% and 5.3% of pCR and non-pCR samples, respectively. No BRCA1 somatic mutations were identified. EGFR, RAD51AP2, SDK2, L1CAM, KPRP, CACNA1S, CFAP58, COL22A1, and COL4A5 were differentially mutated and almost exclusively found in pCR samples. PCDHA1 and TRMT9B were observed in 18.9% and 16.2%, respectively, of non-pCR samples only. There was a trend of higher variant counts in the thirteen matched samples at C1D3 (median of 82, IQR 49-157) versus corresponding pre-treatment samples (median of 72, IQR 42-92), Wilcoxon rank sum test p=0.29, suggesting clone emergence under treatment pressure. Using the Molecular Signatures Database v7.1, several gene families involved in immune related pathways showed differences between pCR and non-pCR samples. Additionally, borderline differences in hedgehog signaling pathway were identified between pCR and non-pCR samples. There were no differences in apoptosis, DNA repair, EMT, inflammatory response, NOTCH signaling pathways. Conclusion: Across TNBC tumors analyzed, TP53 mutation frequency does not differ in pCR versus non-pCR patients. Somatic mutations in EGFR, RAD51AP2, immune pathways genes, and hedgehog signaling pathway genes may predict pCR to docetaxel and carboplatin chemotherapy. Citation Format: Foluso O Ademuyiwa, Jingqin Luo, Bryan Fisk, Gejae Jeffers, Tracy Summa, Isabella Grigsby, Mothaffar Rimawi, Meenakshi Anurag, Matthew Ellis, Obi Griffith, Malachi Griffith. Association between pathological response and tumor genomic profiling in triple negative breast cancer patients treated with neoadjuvant chemotherapy [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 PS18-07.