Primary Tumor Status Research Articles

ADDENDUM TO BREAST CANCER: EVALUATING TUMOR ESTROGEN RECEPTOR STATUS WITH MOLECULAR IMAGING TO INCREASE RESPONSE TO THERAPY AND PATIENT OUTCOMES.

Current statistics show there are 3.5 million women in the United States living with breast cancer today, and approximately 330,000 new cases are diagnosed each year. Of these new cases, 81% are invasive cancers. About 41,000 women die from breast cancer each year. Thankfully, survival rates have increased over the years; however, an accurate diagnosis and treatment plan remain essential for patient survival and longevity. Sometimes breast cancer patients present their medical oncologist with a clinical dilemma on how their particular breast cancer should be treated, especially when standard options fail. Some breast cancer tumors respond to treatment, whereas others do not. Knowing the type of breast tumor a patient has, its estrogen receptor site status, and how it might respond to therapy are vital to effectively and successfully treating the patient, ultimately improving outcomes and overall survival rates. A potential new PET tracer, 18F-fluoroestradiol (currently under Food and Drug Administration review for approval), may be a valuable tool for noninvasive evaluation of the estrogen receptor site status of a patients' primary tumor and secondary metastatic lesions. Imaging estrogen receptor sites is like obtaining a whole-body biopsy that can localize all estrogen-positive lesions in the body, enabling an effective treatment plan to be established for each patient. Estrogen-receptor-site imaging may be beneficial when a tumor is in an inaccessible location or is otherwise difficult to biopsy. Over the years, nuclear medicine has played a crucial role in providing medical oncologists with information helpful for accurately diagnosing and treating patients. With advances in both camera technology and radiopharmaceutical development, the information that nuclear medicine can provide has improved, allowing more accurate treatment and management of patients.

Preliminary Computed Tomography Radiomics Model for Predicting Pretreatment CD8+ T-Cell Infiltration Status for Primary Head and Neck Squamous Cell Carcinoma.

Immunotherapy has emerged as a treatment option for head and neck squamous cell carcinoma (HNSCC), with tumor response being linked to the CD8+ T-cell inflammation. The purpose of this study is to assess whether computed tomography (CT) radiomic analysis can predict CD8+ T-cell enrichment in HNSCC primary tumors. This retrospective study included 71 patients from a head and neck cancer genomics cohort with CD8+ T-cell enrichment status. Pretreatment contrast-enhanced neck CT scans were retrospectively reviewed using 3D Slicer for primary lesion segmentation.The SlicerRadiomics extension was used to extract 107 radiomic features. Ridge regression and lasso regression were applied for feature selection and model construction. Lasso regression defined Coarseness as the most important variable, followed by SmallDependenceEmphasis, SmallAreaLowGrayLevelEmphasis, Contrast.1, and Correlation.Ridge regression defined Coarseness as the most important variable, followed by SmallDependenceLowGrayLevelEmphasis, Contrast.1, DependenceNonUniformityNormalized, and Idmn. These variables identified by lasso and ridge regressions were used to create a combined logistic regression model. The area under the curve (AUC) for the lasso-generated model was 0.786 (95% confidence interval [CI], 0.532-1.000), and the AUC for the ridge-generated model was 0.786 (95% CI, 0.544-1.000). Combining the radiomic variables identified by lasso and ridge regressions with clinical characteristics including alcohol use, tobacco use, anatomic site, and initial T stage produced a model with an AUC of 0.898 (95% CI, 0.731-1.000). T-cell inflammation status of HNSCC primary tumors can be predicted using radiomic analysis of CT imaging and thereby help identify patients who would respond well to immunotherapy.

Efficacy of sentinel lymph node biopsy with radioisotope alone and the prediction of sentinel node status using PET-CT in breast cancer.

Sentinel lymph node biopsy (SLNB) using both a radioactive isotope (RI) and blue dye is considered highly effective; however, there were limitations with the use of both agents in some hospitals, and blue dye has been shown to have some adverse effects. Additionally, preoperative prediction of sentinel lymph node (SLN) status using the maximum standardized uptake value (SUVmax) on positron emission tomography-computed tomography (PET-CT) can help avoid unnecessary axillary dissection or SLNB. Thus, we evaluated the efficacy and oncologic safety of SLNB using an RI alone in terms of long-term outcomes and determined the association between SLN metastasis and SUVmax of the primary tumor. This retrospective study was conducted at Konyang University Hospital between March 2011 and May 2018. Overall, 142 patients with breast cancer who underwent SLNB using an RI alone were enrolled. Data on identification and false-negative rates were collected. The SUVmax of primary tumors on PET-CT were analyzed for their association with SLN metastasis. The identification and false-negative rates were 98.6% and 0%, respectively. There was no axillary local recurrence in patients with negative SLN findings. The correlation between the SUVmax of the primary tumor and SLN status was significant (r=0.249, P=0.005); the cutoff value for negative SLN metastasis was <2.15. The single agent method using an RI is not inferior to other methods and serves as a feasible option for SLNB. And the number of excised SLNs could be minimized when the SUVmax of primary tumor is extremely low.

Regional disease in head and neck cutaneous squamous cell carcinoma: the role of primary tumor characteristics and number of nodal metastases

PurposeTo identify potential risk factors impacting on overall survival (OS) of patients affected by lymph node metastasis from cutaneous squamous cell carcinoma (cSCC) of the head and neck (HN), with special emphasis on primary tumor characteristics and pattern of nodal recurrence (intraparotid and/or cervical).MethodsA bi-institutional retrospective study on consecutive patients affected by cervical and/or intraparotid NM from HN cSCC and surgically treated with curative intent from May 2010 to January 2020 was conducted. OS was considered the outcome of interest.ResultsThe study included 89 patients (M:F = 3.4:1; median age, 78 years; range, 22–99). Among the primary tumor characteristics, the most relevant prognostic factors were diameter ≥ 4 cm (hazard ratio [HR] = 2.56, p = 0.010) and depth of infiltration ≥ 6 mm (HR = 3.54, p = 0.027). Cervical NM was associated with worse OS (HR = 2.09, p = 0.016) compared to purely intraparotid NM (5-year OS: 60.9% vs. 28.1%, p = 0.014). At multivariable analysis, age, immunosuppression, pT3-T4 categories and a high burden of nodal disease (> 2 NM) confirmed to be independent risk factors, whereas adjuvant radiotherapy was independently associated with better outcome.ConclusionThis study confirms the association of several independent prognosticators related to the patient, primary tumor, and nodal burden status. Patients with cervical NM should be considered at risk for harboring a higher number of metastatic lymph nodes.

Retropharyngeal Lymph Node Metastasis Diagnosed by Magnetic Resonance Imaging in Hypopharyngeal Carcinoma: A Retrospective Analysis From Chinese Multi-Center Data.

BackgroundTo assess the prevalence, risk factors and prognostic significance of retropharyngeal lymph node (RPLN) metastasis diagnosed by magnetic resonance imaging (MRI) in patients with hypopharyngeal squamous cell carcinoma (HPSCC).Methods259 patients from three cancer institutions in China from Jan 2010 to Dec 2018 were analyzed, retrospectively. All the patients had been given pre-treatment magnetic resonance imaging (MRI) of head and neck and were then treated with definitive radiotherapy with or without chemotherapy. Pretreatment diagnostic MRIs were reviewed by a dedicated head and neck radiologist, for the presence or absence of radiographically positive RPLN, cervical LN and tumor invasion.Demographic variables were analysed by descriptive statistics using SPSS 20.0. Predictors of the presence of RPLN and its prognostic significance were examined.ResultsRPLN metastasis was discovered in 44 patients (17%). Logistic analysis showed that posterior pharyngeal wall (PPW) primary tumor; PPW invasion; N2-3; multiple cervical lymph node (LN) involvement (>2 LNs) were associated with RPLN metastasis, with metastasis rates 37%, 30%, 31% and 33% respectively. Patients with RPLN metastasis had a significantly reduced 5-year overall survival (OS) and disease-free survival (DFS) compared to the non-RPLN metastasis group (OS 28% vs. 48%, p=0.001; DFS 25% vs. 41%, p=0.040).ConclusionsRPLN metastasis was not uncommon in HPSCC patients. Risk factors were: PPW primary tumor, PPW invasion and cervical LN status. RPLN metastasis is a poor prognosticator for survival.

Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection.

Simple SummaryKRAS mutational heterogeneity between primary colorectal cancer and liver metastases may present a challenge in assessing prognostic information prior to the multimodal treatment. Aim of our study is to assess the incidence of KRAS discordance in a single-center series by comparing primary colorectal tumor specimens with the corresponding liver metastasis. Mutation analyses in all patients were performed at the same institution. Impact of discordance on overall survival and risk factors associated with discordance were analyzed. Our study showed that KRAS discordance was observed in 15.9% of patients. In patients with wild-type colorectal primary tumors, subsequent acquisition of mutation in the corresponding liver metastasis was associated with worse overall survival and was significantly more frequently found in patients with multiple liver metastases. These results suggested that, in the era of precision medicine, the possibility of KRAS discordance should be taken into account within the multidisciplinary management of patients with metastatic colorectal cancer.If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.

Hypofractionated and single-fraction radiosurgery for brain metastases with sex as a key predictor of overall survival

Overall survival (OS) of patients with brain metastases treated with hypofractionated (HFSRT) or single-fraction (SRS) radiosurgery depends on several prognostic factors. The aim of this study was to investigate the potential of sex as an independent predictor of OS and evaluate the predictive accuracy of common prognostic scores. Retrospective analysis of 281 consecutive patients receiving radiosurgery of brain metastases was performed. Kaplan–Meier survival curves and Cox proportional hazards models were used to compare OS between SRS and HFSRT and by sex, before and after propensity-score matching (PSM) on key baseline prognostic covariates. Prognostic scores were evaluated using Harrell’s concordance index. Median OS was 11 months after both SRS and HFSRT. After PSM, median OS was 12 months after SRS (95% CI: 7.5–16.5) and 9 months after HFSRT (95% CI: 5.0–13.0; p = 0.77). Independent prognostic factors were sex, primary tumor, KPI, and systemic disease status. Median OS was 16 months for women and 7 months for male patients (p < 0.001). After excluding sex specific tumors, PSM revealed a median OS of 16 months for women and 8 months for male patients (p < 0.01). Evaluation of prognostic indices showed BSBM to be the most accurate (Harrell’s C = 0.68), followed by SIR (0.61), GPA (0.60), RPA (0.58), and Rades et al. (0.57). OS after HFSRT and SRS did not differ, although PSM revealed a non-significant advantage for SRS. Female sex was found to be a major independent positive prognostic factor for survival, and thus should be considered in the personalized decision-making of brain metastases treatment.

Development of an optimal protocol for molecular profiling of tumor cells in pleural effusions at single-cell level.

Liquid biopsy analyzes the current status of primary tumors and their metastatic regions. We aimed to develop an optimized protocol for single‐cell sequencing of floating tumor cells (FTCs) in pleural effusion as a laboratory test. FTCs were enriched using a negative selection of white blood cells by a magnetic‐activated cell sorting system, and CD45‐negative and cytokeratin‐positive selection using a microfluidic cell separation system with a dielectrophoretic array. The enriched tumor cells were subjected to whole‐genome amplification (WGA) followed by genome sequencing. The FTC analysis detected an EGFR exon 19 deletion in Case 1 (12/19 cells, 63.2%), and EML4‐ALK fusion (17/20 cells, 85%) with an alectinib‐resistant mutation of ALK (p.G1202R) in Case 2. To eliminate WGA‐associated errors and increase the uniformity of the WGA product, the protocol was revised to sequence multiple single FTCs individually. An analytical pipeline, accurate single‐cell mutation detector (ASMD), was developed to identify somatic mutations of FTCs. The large numbers of WGA‐associated errors were cleaned up, and the somatic mutations detected in FTCs by ASMD were concordant with those found in tissue specimens. This protocol is applicable to circulating tumor cells analysis of peripheral blood and expands the possibility of utilizing molecular profiling of cancers.

Evaluating Nationwide Application of Minimally Invasive Surgery for Treatment of Small Bowel Neuroendocrine Neoplasms

AimOpen resection of small bowel neuroendocrine neoplasms (SB-NEN) is still considered standard-of-care, mainly because of frequently encountered multifocality and central mesenteric masses. The aim of this study was to evaluate surgical approach for SB-NEN at a national level and determine predictors for overall survival.MethodsPatients with SB-NEN who underwent resection between 2005 and 2015 were included from the Netherlands Cancer Registry. Patient and tumor characteristics were compared between laparoscopic and open approach. Overall survival was assessed by Kaplan–Meier and compared with the Log-rank test. Independent predictors were determined by Cox proportional hazards model.ResultsIn total, 482 patients were included, of whom 342 (71%) underwent open and 140 (29%) laparoscopic resection. The open resection group had significantly more multifocal tumors resected (24% vs. 14%), pN2 lymph nodes (18% vs. 7%) and stage IV disease (36% vs. 22%). Overall survival after open resection was significantly shorter compared to laparoscopic resection (3-year: 81% vs. 89%, 5-year: 71% vs. 84%, p = 0.004). In multivariable analysis, age above 60-years (60–75, HR 3.38 (95% CI 1.84–6.23); > 75 years, HR 7.63 (95% CI 3.86–15.07)), stage IV disease (HR 1.86 (95% CI 1.18–2.94)) and a laparoscopic approach (HR 0.51 (95% CI 0.28–0.94)) were independently associated with overall survival, whereas multifocal primary tumor, grade and resection margin status were not.ConclusionLaparoscopic resection was the approach in 29% of SB-NEN at a national level with selection of the more favorable patients. Laparoscopic resection remained independently associated with better overall survival besides age and stage, but residual confounding cannot be excluded.

Local treatment of pancreatic cancer metastases: A multicenter French study of the AGEO group

ObjectiveThis study reports the efficacy and safety of local treatment of metastases of pancreatic ductal adenocarcinoma (PDAC), with a curative intent. MethodsWe retrospectively included patients with histologically proven PDAC, who underwent a local treatment for metastases between January 1, 2000 and December 31, 2017, from 11 French hospitals. Complications of local treatment were reported. Univariate Cox models were performed to identify prognosis factors associated with overall survival (OS) and disease-free survival (DFS). ResultsWe included 52 patients treated for 68 metastases; 33 (64%) of whom had metachronous metastases. Metastatic sites treated were: 39 (57%) hepatic, 18 (27%) pulmonary and 11 (16%) others. Metastases treatments were: 45 (66%) surgery, 9 (13%) radiofrequency and 14 (21%) other procedures. The rates of severe complications and mortality were respectively 10% and 4%. The median OS and DFS after local treatment were 36.5 months and 12.7 months, respectively. Prognosis factors associated with a shorter OS were: liver metastases when compared with lung metastases (HR 4.04; 95%CI: 1.18−13.81), N2 status of primary pancreatic tumor when compared to N0–N1 (HR 9.43; 95%CI: 2.44−36.36) and synchronous metastases when compared to metachronous metastases (HR 2.34; 95%CI: 1.05−5.23). N2 status of primary pancreatic tumor was associated with a shorter DFS when compared to N0-N1 (HR 2.82; 95%CI: 1.05–7.58). ConclusionIn this series of highly selected patients, local treatment of metastases from PDAC is associated with prolonged survival. The rate of severe complications was low. Factors associated with shorter OS were liver metastases, N2 status and synchronous metastases.

Abstract PS1-31: Nomogram for predicting axillary lymph node pathological response in node-positive breast cancer patients after neoadjuvant chemotherapy

Abstract Background: Pathological complete response (pCR) of axillary lymph nodes (ALNs) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC). ALN status is an important prognostic factor for choosing the type of axillary lymph node surgery. Many patients with axillary pCR could replace axillary lymph node dissection (ALND) with sentinel lymph node biopsy (SLNB). Our goal is to develop a new predictive clinical model to detect axillary pCR after NAC and provide clinical clues for avoiding ALND. Methods: A retrospective series of 547 patients who had biopsy-proven positive ALNs at diagnosis from 2007 to 2014 in National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences were involved. We analyzed the clinicopathologic features and developed a nomogram to predict the probability of ALN pCR. Univariate assessment was performed using chi-square test. A multivariate logistic regression stepwise model was used to generate a nomogram to predict ALN pCR in node positive patients. The receiver operating characteristic (ROC) curve was established and the area under the curve (AUC) was calculated to evaluate the accuracy of the model. Internal validation was estimated using 50-50 hold out validation method. Nomogram was validated externally with the prospective cohorts of 167 patients from 2016 to 2018 of Cancer Hospital of Chinese Academy of Medical Sciences and 75 patients from 2018 to 2019 of Beijing Tiantan hospital.Results: In the retrospective study, 172 (31.4%) patients achieved axillary pCR after NAC. Multivariate analysis indicated that clinical nodal (N) stage, hormone receptor (HR) status and clinical response of primary tumor after NAC were significant independent predictors for axillary pCR (P&amp;lt;0.05). The AUCs of the internal validation for the training and test sets were 0.719 and 0.753, respectively. The nomogram was validated in external cohorts with AUCs of 0.862 and 0.766, respectively.Conclusion: We developed a nomogram to predict axillary pCR in node positive breast cancer patients after NAC. The predictive model performed well in prospective external validation. This practical tool could provide information to surgeons about whether to avoid ALND after NAC. Citation Format: Xin Wang, Wenyan Wang, Jiaxiang Liu, Xiangzhi Meng, Jiaqi Liu, Changyuan Guo, Ying Song, Ningyi Cui, Qiao Li, Zeyu Xing, Jie Wang, Menglu Zhang, Kexin Feng, Pilin Wang, Xiang Wang. Nomogram for predicting axillary lymph node pathological response in node-positive breast cancer patients after 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 PS1-31.

Analysis of Recurrence in Patients who Underwent Curative-intent Resection for Perihilar Cholangiocarcinoma

Introduction: This study aimed to investigate the patterns of recurrence and to evaluate factors associated with the time to recurrence in resected perihilar cholangiocarcinoma patients. Methods: A retrospective analysis was conducted on 138 patients undergoing curative-intent resection of perihilar cholangiocarcinoma. The median follow-up time was 115 months. Results: During the follow-up period, 77 patients (56%) relapsed and the 5-year recurrence rate was 61%. Of 77 patients, 71 (92%) relapsed within 5-years after resection. Distant recurrence was detected in 44 patients (57%), whilst locoregional recurrence in 21 patients (27%), and the both in 12 patients (16%). The sites of distant recurrence were the liver (n = 17), peritoneum (n = 16), distant lymph nodes (n = 14), and lung (n = 9). On multivariate analysis, age (hazard ratio [HR] 1.7, P = 0.039), venous invasion (HR 1.9, P = 0.01), primary tumor status (HR 2.2, P = 0.001), and number of positive nodes (1-3: HR 1.8, P = 0.001, ≥ 4: HR 3.7, P = 0.028) were independent factors associated with time to recurrence. The treatment for the 77 relapsed patients were surgery (n = 8), chemotherapy (n = 41), and best supportive care (n = 28). The 3-year overall survival after recurrence was 38%, 4%, and 0%, respectively (P < 0.001). Conclusions: More than half of patients with perihilar cholangiocarcinoma experience recurrence after curative-intent surgery, and these recurrences occur mostly within 5 years. Adjuvant strategies should be considered, especially for patients with venous invasion, extensive primary tumor, and nodal metastasis.

Expression of Biomarkers Estrogen Receptor, Progesterone Receptor, HER2 in Primary Breast Tumour and Synchronous Metastatic Axillary Lymph Node

Introduction: Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2) status are routinely used to guide treatment decision for breast cancer. Treatment protocol in breast cancer is currently based on biomarker characteristic of primary tumour. But this biomarker status may change as the tumour progresses from primary to synchronous metastatic lymph node. Hence, it is important to know the biomarker status of these synchronous metastatic lymph nodes as it may serve as an important tool to guide management, evaluate prognosis and to anticipate the possibility of recurrent risk of primary invasive breast cancer. Aim: To study the expression of ER, PR, HER2 status in primary breast carcinoma and synchronous metastatic lymph node and to evaluate concordance and discordance between them. Materials and Methods: This study was observational, retrospective and prospective study conducted over a period of one and half years from February 2015 to October 2016 at ESI-PGIMSR, Maniktala, Kolkata, India, where 50 cases of breast carcinoma with positive axillary lymph node metastasis were studied. Haematoxylin and Eosin (H&amp;E) sections were reviewed and representative paraffin blocks were selected. Immunostains were performed and scoring was done following standard protocols. Standard statistical methods were applied for analysis of data using chi-square test and kappa statistics and data was analysed using Statistical Package for the Social Sciences (SPSS) version 6.1.3 software. Results: Out of 50 cases the mean age of the patients was 50.56±10.5 years. Amongst ER and PR status, 24 out of 50 (48%) and 18 out of 50 (36%) were ER and PR positive respectively. HER2 positive cases were 48% i.e., 24 out of 50 cases. The overall discordance rates of ER, PR and HER2 was found to be 10%, 8%, 18%, respectively. The discordance rates of ER positive and ER negative cases were 4.2% and 15.4%, respectively. The discordance rates of PR positive and PR negative cases were 5.6% and 9.4% respectively, whereas 29.2% of HER2 positive cases were discordant in lymph node metastases. Conclusion: There was discordance between ER, PR, HER2 status of primary tumour and metastatic lymph node. Hence, assessment of these biomarker status in axillary lymph node metastases may be considered along with primary tumour in breast carcinoma work-up.

PO-0898: Primary tumor-status relevance in NSCLC with brain metastases undergoing radiosurgery

PO-0898: Primary tumor-status relevance in NSCLC with brain metastases undergoing radiosurgery

INFLUENCE OF SOMATIC MUTATIONS OF KRAS, NRAS, BRAF AND MICROSATELLITE INSTABILITY STATUS ON SURVIVAL OF COLORECTAL CANCER PATIENTS WITH PERITONAL CARCINO

Purpose: to evaluate the effect of somatic mutations of the KRAS, NRAS, BRAF genes and the status of microsatellite instability on the overall and disease-free survival of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.Material and Methods. From 2012 to 2018, the study included 45 patients who underwent surgery for synchronous peritoneal carcinomatosis with colorectal cancer. In all patients, mutations of the KRAS, NRAS, BRAF genes and MSI status of the tumor and peritoneum metastases were determined using Sanger sequencing, fragment analysis and digital droplet polymerase chain reaction. The effect of mutations on patient survival was evaluated.Results. The prevalence of somatic mutations was 69 % of patients. The discordance between the tumor and peritoneum metastases was 9 %. All tumors and peritoneum metastases were microsatellite stable. KRAS, NRAS, BRAF mutations did not affect the overall and disease-free survival (p=0.87 and p=0.85, respectively).Conclusion. Somatic mutations in the KRAS, NRAS, or BRAF genes are not a prognostic factor affecting the overall and relapse-free survival of colorectal cancer patients with peritoneal carcinomatosis. The molecular status of primary tumor may differ from the status of peritoneal metastasis. It should be taken into account when prescribing targeted drugs.

Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study

BackgroundMaintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. MethodsBEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) – but remains unresectable – after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.

Diagnostic and Predictive Values of 18F-FDG PET/CT Metabolic Parameters in EGFR-Mutated Advanced Lung Adenocarcinoma.

PurposeThe clinical implications of the metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in epidermal growth factor receptor (EGFR)-mutated lung cancer are not fully understood. The aim of this study was to evaluate the diagnostic and prognostic utility of the parameters in EGFR-mutated lung cancer patients.Patients and MethodsWe retrospectively enrolled 134 patients with advanced lung adenocarcinoma (72 EGFR-negative and 62 EGFR-positive). We evaluated the correlation between EGFR mutational status and the maximum standardized uptake value (SUVmax), as well as the associations between treatment outcomes in EGFR-mutated patients and various metabolic parameters of primary tumors. For the best predictive parameters, we calculated the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) using two SUV cutoffs: 1.5 (MTV1.5, TLG1.5) and 2.5 (MTV2.5, TLG2.5).ResultsMean SUVmax was lower for EGFR-mutated tumors compared with EGFR wild-type (6.11 vs 10.41, p < 0.001) tumors. Low SUVmax was significantly associated with positive EGFR mutation (odds ratio = 1.74). Multivariate analysis for survival demonstrated that high MTV1.5, TLG1.5, MTV2.5, and TLG2.5 were independently associated with shorter progression-free survival (PFS) and overall survival (OS), and the highest hazard ratios were found in TLG1.5 (3.26 for PFS and 4.62 for OS).ConclusionSUVmax may be predictive for EGFR mutational status, and MTV and TLG of primary tumors may be promising prognostic parameters; 18F-FDG PET/CT has potential utility for the risk stratification of EGFR-mutated patients treated with targeted therapy.

Unknown primary tumor high-risk melanoma as a unique patient population with distinct prognosis in the adjuvant setting: An ECOG-ACRIN E1609 study analysis.

e22090 Background: E1609 enrolled 1670 adult patients (pts) with resected AJCC7 stages IIIB, IIIC, M1a, M1b melanoma and compared adjuvant ipilimumab at 3 or 10 mg/kg (ipi3 and ipi10) to high dose interferon-alfa (HDI). With over 5 years of follow up, the risk of relapse and death by primary tumor status and by stage group is expected to inform the design of future adjuvant trials and ultimately, clinical practice. Methods: Unknown primary melanoma status was defined as initial presentation with cutaneous, nodal or lung metastasis that was completely resected without a history of known primary melanoma. We evaluated the pt distribution by the initial site of metastasis. Further, we evaluated the risk of relapse and death by primary tumor status and by stage group. Five-year relapse-free survival (RFS) and overall survival (OS) rates and 95% CIs were estimated by Kaplan-Meier method. Stratified (by stage) log-rank test was used to compare RFS and OS by primary tumor status. Two-sided p-values were derived. Results: Unknown primary melanoma represented 12.8% of the total study population including 11.7% on the ipi arms and 14.7% on HDI. Site of metastasis at initial presentation among unknown primary cases included cutaneous and nodal (97%) and lung (3%). Among the overall study population, M1a stage group included the highest proportion of pts with unknown primary (42.2%). Stratifying by stage, RFS (p = 0.001) and OS (p = 0.009) were significantly better for pts with unknown primary compared to known primary. Including only ipi3 and ipi10 pts, RFS (p = 0.005) and OS (p = 0.023) were consistently significantly better in favor of unknown primary. Five-year RFS and OS rates by primary tumor status and stage group among pts treated with ipi (ipi3 and ipi10) are summarized in Table. Conclusions: Unknown primary status represents a unique population among high-risk melanoma pts treated with ipi with improved RFS and OS outcomes that support their separate assessment in future immunotherapy adjuvant trials. In-depth analyses of the tumor biology and host immunology are ongoing. Outcome analyses by the overall study stage groups and the HDI arm will be reported at the meeting. Clinical trial information: NCT01274338. [Table: see text]

Chick chorioallantoic membrane (CAM) assays as a model of xenografts derived from circulating cancer stem cells from breast cancer patients.

e15596 Background: Circulating cancer stem cells (cCSCs) are a rare fraction of circulating tumor cells with a profile of stemness, resistance to chemotherapy and the capacity to generate metastases. Patient-derived xenografts (PDX) are an increasingly noticed tool in oncology, providing biologically meaningful models of many cancer types, and potential platforms for the development of precision oncology approaches. Commonly, mouse models are used for the in vivo assessment of potential new therapeutic targets in cancers. However, given the high cost, time investment, and legal obligations of such animal models CAM assays are an attractive alternative. Methods: In this study, primary cultures from circulating cancer stem cells were established using sphere-forming assays. Subsequently, tumorspheres were transplanted onto the CAM membrane of fertilized chicken eggs to form secondary microtumors. Results: We have developed an innovative in vitro platform for cultivation of CSCs from peripheral blood of breast cancer patients. The number of tumorspheres increased significantly with tumor progression. Patients with metastatic disease had statistically more tumorspheres as compared to patients without metastasis (30 vs 10/100µl blood, p &lt; 0.05). Patients with multiple metastases had more tumorspheres compared to patients with single metastases (30 vs 60/100µl blood, p &lt; 0.05). The number of tumorspheres was positively correlated with Ki-67, Her2 status and grade score in primary breast tumors. Tumorspheres showed self-renewal, growth potentials, invasion and differentiation in vivo. Their transplantation on CAM membranes resulted in the rapid formation of microtumors in many cases. These tumors pathologically closely resembled the primary tumor. The success rate of PDX was positively correlated with aggressiveness and proliferation capacity of the primary tumor. Conclusions: The number of tumorspheres cultured from peripheral blood of cancer patients and the success rate of establishing PDX directly reflect the aggressiveness and proliferation capacity of the primary tumor. A CAM-based PDX model using circulating cancer stem cells provides a fast, low-cost, easy to handle and powerful preclinical platform for drug screening, therapy optimization, and biomarker discovery.

A Simple and Practical Scoring System for Radiosurgical Treatment in Patients with Brain Metastases

Background: The study aimed to investigate the prognostic factors for patients with brain metastases undergoing radiosurgical treatment and to introduce a simple and practical scoring system for the prediction of survival time. Methods: We retrospectively analyzed data for 311 patients treated with Gamma Knife radiosurgery at a single institute. The mean age at time of treatment was 60 years (range 23–86 years), and the median Karnofsky performance status (KPS) score was 90 (range 60–100). Using a new prognostic index, the prognostic index for brain metastases (PIBM), the patients were categorized into 3 groups according to the primary tumor status and KPS score. We performed survival analysis and compared the prognostic ability of the PIBM with other published indices. Results: During the median follow-up duration of 8.2 months (range 0.1–109 months), the median overall survival time was 9.1 months. Stable primary tumor status (hazard ratio [HR] 0.497, 95% confidence interval [CI] 0.321–0.769, p = 0.002) and KPS score ≥90 (HR 1.407, 95% CI 1.018–1.946, p = 0.039) significantly predicted longer overall survival. The PIBM showed the lowest Akaike information criterion value and the highest integrated area under the curve value compared with other prognostic indices. Conclusions: The PIBM may be a more accurate prognostic indicator than other published indices. Although this new and practical prognostic index requires further validation in larger cohort studies, we suggest that the PIBM could be useful to predict survival time and inform appropriate management of patients with brain metastases.