Overall Survival In Metastatic Patients Research Articles

A Case Report of Unrespectable Liver Metastases from Cancer Rectosigmoid Colon with Survival Greater Than 6 Years and Clinical Benefit after Multidisciplinary Treatment

Introduction Colorectal cancer represents 1,271 new cases per year in Morocco, However, over the last 30 years we have witnessed a significant increase in the overall survival of metastatic patients due to the arrival of new molecules.  Case Presentation We report the case of a 51 years old african female patient diagnosed for a moderately differentiated adenocarcinoma of the rectosigmoid junction MSS, wild RAS/BRAF, treated with colorectal protection and lymph node dissection, followed by 6 cycles of fulfol- cisplatin as an adjuvant. the follow up revealed the appearance of hepatic masses. The liver biopsy was performed showing a secondary localization of an adenocarcinoma of digestive origin. The patient received four lines of the chemotherapy, anti-EGFR antibodies and immunotherapy following the guidelines. However, since no KRAS NRAS BRAF mutation was detected at the DNA level circulating tumor, no rechallenging of the anti- EGFR was possible. The hepatic progression continued with appearance of pulmonary lesions, the decision was made for a palliative care.  Conclusion Our case highlights that due to the emergence of new effective molecules currently available, associated with a dedicated onco-surgical approach, more patients will be able to benefit from prolonged survival that did not seem achievable at the time of diagnosis.

THU616 Analysis Of Germline Mutations In Patients With Sporadic Adrenocortical Carcinoma

Abstract Disclosure: M. Terzolo: None. S. Grisanti: None. M. Scatolini: None. P. Tomaiuolo: None. E. Grosso: None. V. Basile: None. D. Cosentini: None. S. Puglisi: None. M. Laganà: None. P. Perotti: None. L. Saba: None. E. Rossini: None. S. Sigala: None. M. Volante: None. A. Berruti: None. Background: Adrenocortical carcinoma (ACC) is a rare cancer associated with hereditary syndromes in 10% of cases. Germline variants (GVs) in patients with ACC have been identified mainly in pediatric patients and in family cases, while data on GVs in adult patients with sporadic ACC are limited. Methods: We analyzed germline DNA from 150 adult patients with sporadic ACC sequentially referred to our centers between 1998 and 2019. We designed a custom panel of 17 genes potentially involved in the pathogenesis of ACC: AIP, APC, ARMC5, ARNT, BRCA1, BRCA2, CTNNB1, IGF2, MEN1, MSH2, MSH6, PDE8B, PDE11A, PRKACA, PRKACB, PRKAR1A, and TP53. NGS data were analyzed by a semi-automated bioinformatic pipeline. All GVs were studied using effect predictor tools (PolyPhen and SIFT). Specific databases (ClinVar, Varsome, gnomAD, IARC TP53, HGMD) were used for variant classification according to ACMG criteria. Variants interpreted as pathogenic (P) or likely pathogenic (LP) were considered as positive. Clinical, pathological and genomic data were analyzed in different Cox models to study prognostic impact of covariates for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS). Results: We identified 21 unique GVs in 24/150 patients (16%). GVs were found in 9 genes including APC (n=3), ARMC5 (n=3), MSH2 (n=3), PDE11A (n=3), TP53 (n=3), MSH6 (n=2), PDE8B (n=2), AIP (n=1) and CTNNB1 (n=1). Eleven positive GVs including 3 GVs with deleterious potential were found in 14/150 patients (9.3%). Some variants were particularly enriched, with a frequency of 0.02% compared to an overall frequency of 0.001-0.004% in the gnomAD database. We found a new GV in TP53 (G105D) in a patient who was later found to have a sister with ACC and, for the first time, 3 GVs in ARMC5 (P731R). Patients with ARMC5 GVs had large cortisol-secreting tumors and one case displayed pathologic features of ACC and combined macronodular cortical disease. Positive GVs were associated with a shorter OS (50 vs 142 months, HR 1.81; 95%CI, 0.86-3.82, p=0.118) and PFS (8 vs 30 months, HR 3.11; 95%CI, 1.57-6.16, p=0.001) but not DFS (27 vs 32 months, HR 1.07; 95%CI, 0.52-2.22, p=0.845). At multivariate analysis, known clinical factors (age, surgery of primary ACC, ENSAT stage, hypercortisolism) were found to have prognostic impact on OS. However, GVs remained independent predictors of PFS and OS in metastatic patients. Conclusions: In a series of 150 patients with ACC, we found that 9.3% of them had positive GVs, thus confirming findings from the TCGA analysis. We describe for the first time the presence of ARMC5 GVs in patients with ACC and we found a novel pathogenic variant of TP53. Pathologic features of one ARMC5 case suggest a possible progression from macronodular hyperplasia to ACC. Finally, the present findings suggest that GVs can affect ACC progression and survival of affected patients. Presentation: Thursday, June 15, 2023

P132 Prognosis and molecular characteristics of IBD-associated colorectal cancer: experience from a French tertiary-care center

Abstract Background Little is known about the prognosis of colorectal cancer associated with inflammatory bowel disease (CRC-IBD) in a real-world cohort in France. Methods We conducted a retrospective observational study including all patients presenting CRC-IBD in a tertiary French center between 1990 and 2021. Clinical and molecular data were collected. We analyzed overall survival (OS), progression free survival (PFS) and factors associated with prognosis. Outcome probabilities were analyzed using the Kaplan-Meier method. Results Among 6510 patients, the incidence rate of CRC was 0.8% (N =49) with a median delay of 19.5 years after IBD diagnosis. The median age was 46 years, the main IBD was ulcerative colitis (59%), the primary tumor was rectal in 49% and localized at diagnosis in 69%. There was a previous exposure to immunosuppressants (IS) in 57% and anti-TNF in 29% of the cases. The most frequent mutation was TP53 (56%). A RAS mutation was observed in 37% of the whole population and 13% of metastatic patients. OS of the whole cohort was 45 months OS and PFS of synchronous metastatic patients was 20.4 months and 8.5 months respectively. Among the patients with localized tumor those previously exposed to IS had a better progression-free survival (39 months vs 23 months; p =0.05) and a better OS (74 vs 44 months; p =0.03). Only 2 patients (4%) experienced IBD relapse during follow-up despite IS and biologics discontinuation in all exposed patients. Chemotherapy exposure was 53% and 93% in the adjuvant and metastatic setting respectively. No unexpected side-effect was observed, the only reason for discontinuation was oxaliplatin-sensitive neuropathy. Conclusion Incidence of CRC is elevated in IBD patients with a poor OS in metastatic patients although IBD is not associated with under-exposure or increased toxicity to chemotherapy. Previous IS exposure may be associated with a better prognosis.

Causes of death and conditional survival estimates of long-term lung cancer survivors.

IntroductionLung cancer ranks the leading cause of cancer-related death worldwide. This retrospective cohort study was designed to determine time-dependent death hazards of diverse causes and conditional survival of lung cancer.MethodsWe collected 816,436 lung cancer cases during 2000-2015 in the SEER database, after exclusion, 612,100 cases were enrolled for data analyses. Cancer-specific survival, overall survival and dynamic death hazard were assessed in this study. Additionally, based on the FDA approval time of Nivolumab in 2015, we evaluated the effect of immunotherapy on metastatic patients’ survival by comparing cases in 2016-2018 (immunotherapy era, n=7135) and those in 2013-2016 (non-immunotherapy era, n=42061).ResultsOf the 612,100 patients, 285,705 were women, the mean (SD) age was 68.3 (11.0) years old. 252,558 patients were characterized as lung adenocarcinoma, 133,302 cases were lung squamous cell carcinoma, and only 78,700 cases were small cell lung carcinomas. TNM stage was I in 140,518 cases, II in 38,225 cases, III in 159,095 cases, and IV in 274,262 patients. 164,394 cases underwent surgical intervention. The 5-y overall survival and cancer-specific survival were 54.2% and 73.8%, respectively. The 5-y conditional survival rate of cancer-specific survival is improved in a time-dependent pattern, while conditional overall survival tends to be steady after 5-y follow-up. Except from age, hazard disparities of other risk factors (such as stage and surgery) diminished over time according to the conditional survival curves. After 8 years since diagnosis, mortality hazard from other causes became higher than that from lung cancer. This critical time point was earlier in elder patients while was postponed in patients with advanced stages. Moreover, both cancer-specific survival and overall survival of metastatic patients in immunotherapy era were significantly better than those in non-immunotherapy era (P<0.001), indicating that immunotherapeutic intervention indeed bring remarkable benefits to advanced lung cancer patients.ConclusionsOur findings expand on previous studies by demonstrating that non-lung-cancer related death risk becomes more and more predominant over the course of follow-up, and we establish a personalized web-based calculator to determine this critical time point for long-term survivors. We also confirmed the survival benefit of advanced lung cancer patients in immunotherapy era.

Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study

Background and Aims: Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. Methods: Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. Results: Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS-mutated tumours were associated with reduced DFS (p = 0.02) and OS (p = 0.045) in stage I–III CRC. BRAF-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in BRAF-mutated tumours in contrast to 18.6 months in BRAF wild-type tumours (p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. Conclusion: In our cohort, RAS-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

Evaluation of dystrophin expression by immunohistochemistry as a prognostic factor in leiomyosarcomas (LMS).

e23525 Background: Leiomyosarcomas (LMS) are soft tissue sarcomas that derive from smooth muscle cells and can arise anywhere in the body (most frequently in extremities, uterus or retroperitoneum). The clinical prognostic factors are well established but molecular factors influencing prognostic are unknown. The DMD gene, which codifies for the dystrophin protein, has been proposed as tumour suppressor gene in LMS. The aim of our study is to evaluate dystrophin expression in LMS and its relation with the patient prognosis. Methods: A total of 103 patients (pts) with LMS were analysed. Clinical and pathological data were collected retrospectively from patients’ electronic board system. Dystrophin expression was analysed by immunohistochemistry (IHC) in paraffin embedded tissue LMS samples using the Novocastra NCL-DYS2 (Leica Biosystems). Semiquantitative assessment of the staining was classified from score 0 to 3 (0 = no dystrophin expression, 1 = low expression, 2 = moderate expression, 3 = high expression). Results: Of all 103 pts, 70 (68%) had localized disease and the majority of tumours were larger than 5 cm (75%). The most frequent locations of primary LMS were extremities (n = 31; 30.1%), uterus (n = 23; 23.2%) and retroperitoneum (n = 21; 20.4%). Most LMS were high grade (G): 7 pts G1 (6.8%), 35 pts G2 (34%) 2 and 53 pts G3 (51.5%). 50 of all grade LMS (48.6%) had loss of dystrophin expression (score 0), 17 (16.5%) had score 1, 23 (22.3%) score 2 and 10 (9.7%) score 3. Loss/low dystrophin expression measured as score 0 or 1, was more frequent in grade 3 LMS compared to grade 2 or grade 1 (77.4% vs. 57.1% vs. 16.7%; p = 0.005). There were no differences in dystrophin loss between localized or metastatic disease at diagnosis (64.2% vs. 72.2%; p &gt; 0.05). In our series, loss or reduced dystrophin expression did not correlate with the risk of relapse in localized patients or overall survival in metastatic patients. Conclusions: Loss of dystrophin expression is a common event in LMS. Loss/low dystrophin expression is more frequent in grade 3 LMS compared to grade 2 and grade 1 LMS. Loss of dystrophin expression did not correlate with risk of relapse or overall survival in our series. Additional genetic evaluations to study DMD in LMS are underway.

Pancreatic acinar cell carcinoma: A multi-center series on clinical characteristics and treatment outcomes.

e16253 Background: Acinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series. Methods: This is a retrospective study conducted at a large healthcare system from 1996-2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test. Results: Sixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery conferred OS benefit in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy provided OS benefit in metastatic disease (p &lt; 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006). Conclusions: Pancreatic ACC patients often present with advanced disease. Surgery confers survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

Pancreatic acinar cell carcinoma: A multi-center series on clinical characteristics and treatment outcomes

BackgroundAcinar cell carcinoma (ACC) is a very rare tumor of the exocrine pancreas, representing less than 1% of all pancreatic malignancies. The majority of data regarding ACC are limited to small case series. MethodsThis is a retrospective study conducted at a large healthcare system from 1996 to 2019. Patients with pathologically confirmed ACC were included, and demographic data, tumor characteristics, and treatment outcomes were abstracted by chart review. Survival curves were obtained by using the Kaplan-Meier method and compared using the log-rank test. ResultsSixty-six patients with ACC were identified. The median patient age at diagnosis was 64, and 42% presented with metastatic disease. The majority presented with abdominal pain or pancreatitis (69%), and laboratory parameters did not correlate with tumor size, metastatic disease, or survival. Several somatic abnormalities were noted in tumors (BRCA2, TP53, and mismatch-repair genes). In patients with localized disease that underwent resection, the median time to develop metastatic lesions was 13 months. The median overall survival (OS) was 24.7 months from diagnosis, with a survival difference based on metastatic disease at diagnosis (median 15 vs 38 mos). Surgery was associated with improved survival in non-metastatic cases (p = 0.006) but not metastatic cases (p = 0.22), and chemotherapy showed OS benefit in metastatic disease (p < 0.01). Patients with metastatic ACC treated after 2010 utilized more platinum-based agents, and there was a OS benefit to FOLFOX or FOLFIRINOX chemotherapy compared to gemcitabine or capecitabine-based regimens (p = 0.006). ConclusionPancreatic ACC patients often present with advanced disease. Surgery was associated with survival benefit among patients presenting with localized disease. The use of FOLFOX or FOLFIRINOX chemotherapy regimens was associated with improved OS in metastatic patients. These data add to our knowledge in this rare malignancy, and improves understanding about the genomic underpinnings, prognosis and treatment for acinar cancers.

The role of immunotherapy in metastatic triple negative breast cancer: a narrative review of the current clinical trials

: Triple negative breast cancer is an aggressive subtype of breast cancer that lacks expression of estrogen and progesterone receptors, and does not overexpress the human epithelial growth factor 2 receptor. Triple negative breast cancer occurs in approximately 20% of breast cancer cases, and patients are more likely to present with an advanced stage, have higher relapse rates, and have a worse prognosis than other breast cancer types. There are no targeted therapies for the majority of patients with triple negative breast cancer. The mainstay of treatment remains chemotherapy and the historical median overall survival for metastatic patients is around one year. Immunotherapy has dramatically improved outcomes in other malignancies by harnessing the body’s immune system to attack cancer cells. Triple negative breast cancer is the most immunogenic type of breast cancer, with a large genetic mutational burden and a relatively high number of immune cells found in the cancer microenvironment compared to other breast cancer subtypes. While initial studies of single agent immunotherapy in metastatic triple negative breast cancer were promising, the survival outcomes have been disappointing. Combining systemic therapy with immunotherapy has become a recent focus of clinical trials, and is now the current standard of care for treatment naive metastatic triple negative patients that are programmed death-ligand 1 positive. The efficacy of combined chemoimmunotherapy for first-line treatment has yet to be replicated, and recent clinical data questions the true benefit. This review summarizes the clinical trials of single agent and combination strategies for immunotherapy in metastatic triple negative breast cancer. We also examine the potential role for biomarkers, and future direction of treatment.

MET exon 14 skipping mutation positive non-small cell lung cancer: Response to systemic therapy

ObjectivesMET exon 14 skipping is a potentially targetable molecular alteration. The goals of this study were to identify patients treated in British Columbia with MET exon 14 skipping to understand prevalence, biology and response to treatment, and to identify molecular signatures that may predict for response or resistance to targeted MET therapy in the setting of advanced disease. Materials and MethodsA retrospective review was completed of patients found to have MET exon 14 skipping alterations between January 2016-September 2019. Information was collected on baseline characteristics, response to systemic treatments, and outcomes. ResultsOut of 1934 advanced, non-squamous and never-smoking squamous NSCLC patients tested, 41 patients were found to have MET exon 14 skipping (2.1 %). MET alteration types: 2% CBL binding-domain mutations, 34 % poly-pyrimidine tract deletions, 63 % splice donor mutations or deletions. The most common co-mutation was TP53 (22 %). Thirty-three patients received systemic therapy. Physician-assessed disease control was 68 % among 19 evaluable patients treated with crizotinib, 80 % among 10 evaluable patients treated with platinum-based chemotherapy, and 70 % among 10 evaluable patients treated with immunotherapy. Median time to treatment discontinuation was 3.0, 2.8, and 2.4 months, respectively. Median overall survival for metastatic patients treated with any systemic therapy was 15.4 months. In this small cohort, there were no clear correlations between molecular aberrations and response, time to treatment discontinuation, or survival for crizotinib, chemotherapy, and immunotherapy. ConclusionThe prevalence of MET exon 14 skipping in a North American population was 2.1 %. Unlike other targetable mutations, patients were older and more commonly current or former smokers. Patients with MET exon 14 skipping alteration demonstrate disease control with crizotinib, platinum-based chemotherapy and immunotherapy. Co-mutations with TP53 were commonly noted, but correlation between co-mutations and efficacy of therapy were not identified in this cohort.

Abstract B075: Defining germline mutations of DNA damage repair genes in African American prostate cancer patients

Abstract Background: DNA damage repair genes (DDRGs) play a critical role in protecting genome integrity and have been implicated in several cancer types. In the context of prostate cancer (CaP) emerging data provide potential role of this pathway in aggressive disease. It has also been recently demonstrated that PARP inhibitors can extend overall survival in metastatic patients with DDRG mutations. However, the association and therapeutic stratification based on inherited mutations of DDRGs remains to be defined in African American (AA) CaP patients. Our objective was to assess the frequency and association with disease aggressiveness of all known DDRGs in blood derived genomic DNAs of AA and Caucasian American (CA) CaP patients archived at the DOD Center for Prostate Disease Research and assess how this information can refine patient stratification for specific targeted therapeutic options. Method: Germline mutations in all DDRGs was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 CaP patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center (WRNMMC) over the past 20 years. These patients had equal access Department of Defense healthcare system with up to 20 years of follow-up time. Following quality control steps to assess DNA quantity by Qubit assay and DNA quality by Bioanalyzer assay, DNA samples were used to generate PCR-free libraries for WGS using the NovaSeq (Illumina) platform. Out of the 600 libraries we generated, 14 dropped out, achieving a success rate of 97.6%. The successful libraries had an excellent quality based on DNA library metrics (yield and fragment length). Whole genome sequencing depth of the samples exceeded 37x on average and about 4 million SNPs were identified in the samples. Patient genotypes were projected onto principal components from reference populations. Sample ancestries were predicted by using the “Peddy” program, which uses a machine learning model trained on individuals of diverse ancestries from the 1000 Genomes Project reference panel. Due to mismatched ancestry, 33 samples were excluded from further analyses. An additional 17 samples were excluded due to higher than minimal noise level based on analyses using “ContEst” tool from Broad GATK package and Illumina noise percent values. Results: Interrogation of an inclusive DDRG set of 180 genes predicted to have non-silent effects on the protein sequence (e.g. missense, nonsense, frameshift) for germline mutations in this cohort revealed several known and novel mutations. The analysis has not been finalized yet. Mutation data will be assessed for association with the extensive available clinical and pathological data, including disease progression (metastasis), family history and African ancestry. Novel mutations, anticipated especially in the understudied AA context, will be analyzed for functional impact. Citation Format: Kevin Babcock, Xijun Zhang, Matthew Wilkerson, Clifton L. Dalgard, Shyh-Han Tan, Lakshmi Ravindranath, Yongmei Chen, Jennifer Cullen, Shiv Srivastava, Inger L. Rosner, Gyorgy Petrovics. Defining germline mutations of DNA damage repair genes in African American prostate cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B075.

Early recognition of anorexia through patient-generated assessment predicts survival in patients with oesophagogastric cancer.

Cancer cachexia is common in patients with oesophagogastric cancer (OG) and is linked to overall survival (OS). One of the key components of cachexia is anorexia; it is not known whether anorexia impacts on OS and there is no method of routine screening in current practice. Diagnosis relies on patients describing the symptoms, clinicians diagnosing anorexia and acting upon it. Patients with oesophageal/gastroesophageal junction or gastric cancer were assessed using the Functional Assessment of Anorexia Cachexia Therapy Anorexia/Cachexia Subscale (FAACT A/CS). FAACT A/CS includes 12 questions validated previously to diagnose anorexia in patients with cancer. Of the 182 patients included, 69% scored ≤37/48 and were considered to be anorexic; FAACT A/CS was a better predictor of OS in metastatic patients than body mass index or weight loss in the six months prior to cancer diagnosis. The median OS of patients with FAACT A/CS scores of >37 was longer than patients with scores of ≤37 (19.3 months vs 6.7 months, Hazard Ratio [HR] 2.9, 95% Confidence Interval [CI] 1.4–6.0, p<0.0001). Patients with performance status (PS) 0–2 and FAACT A/CS >37 had substantially longer OS than those with PS 0–2 and FAACT A/CS ≤37 (18.7 months vs 7.9 months, HR 2.5 (95% CI 1.2–5.1, P<0.0001). The FAACT A/CS questionnaire allows clinicians to identify patients with anorexia who may benefit from early nutrition interventions. Importantly, this is the first study to show the association between anorexia and survival in patients with metastatic OG cancers. This will form the basis of future interventional studies to improve patient outcomes.

Association of Insurance Status With Presentation, Treatment, and Survival in Melanoma in the Era of Immune Checkpoint Inhibitors.

The effect of health insurance on management and outcomes in melanoma is unclear. Using the National Cancer Database (NCDB), we evaluated the effect of insurance on (1) stage at diagnosis, (2) receipt of immunotherapy, and (3) overall survival (OS) among patients with melanoma. We included patients with stage I-IV melanoma diagnosed from 2011 to 2015. Patients were stratified by age (below 65 vs. 65 y or above) and insurance (commercial, Medicare, Medicaid and uninsured). We evaluated the association between insurance and (1) stage at diagnosis (stage I-III vs. IV) and (2) receipt of immunotherapy (stage IV) using multivariable logistic regression. The association of insurance status with OS in metastatic patients who received immunotherapy was assessed using Kaplan-Meier and Cox proportional hazards analyses. The study included 167,130 patients; 52% had commercial insurance, 43% had Medicare, 3% had Medicaid and 2% were uninsured. In patients below 65 years, those with Medicaid and the uninsured had a higher likelihood of presenting with metastatic melanoma and were less likely to receive immunotherapy compared with those with commercial insurance. Further among those who received immunotherapy, patients with Medicaid (hazard ratio: 1.51, P=0.001) and no insurance (hazard ratio: 1.37, P=0.046) had an inferior OS. In patients 65 years or above, whereas Medicare was associated with an increased likelihood of presenting with metastatic disease, there was no significant difference in receipt of immunotherapy or OS as compared with commercial insurance. In this large modern cohort, insurance was associated with stage at diagnosis, receipt of immunotherapy, and OS for patients below 65 years old with melanoma.

VEGFC acts as a double-edged sword in renal cell carcinoma aggressiveness.

Hypoxic zones are common features of metastatic tumors. Due to inactivation of the von Hippel-Lindau gene (VHL), renal cell carcinomas (RCC) show constitutive stabilization of the alpha subunit of the hypoxia-inducible factor (HIF). Thus, RCC represents a model of chronic hypoxia. Development of the lymphatic network is dependent on vascular endothelial growth factor C (VEGFC) and lies at the front line of metastatic spreading. Here, we addressed the role of VEGFC in RCC aggressiveness and the regulation of its expression in hypoxia.Methods: Transcriptional and post transcriptional regulation of VEGFC expression was evaluated by qPCR and with reporter genes. The involvement of HIF was evaluated using a siRNA approach. Experimental RCC were performed with immuno-competent/deficient mice using human and mouse cells knocked-out for the VEGFC gene by a CRISPR/Cas9 method. The VEGFC axis was analyzed with an online available data base (TCGA) and using an independent cohort of patients.Results: Hypoxia induced VEGFC protein expression but down-regulated VEGFC gene transcription and mRNA stability. Increased proliferation, migration, over-activation of the AKT signaling pathway and enhanced expression of mesenchymal markers characterized VEGFC-/- cells. VEGFC-/- cells did not form tumors in immuno-deficient mice but developed aggressive tumors in immuno-competent mice. These tumors showed down-regulation of markers of activated lymphocytes and M1 macrophages, and up-regulation of M2 macrophages markers and programmed death ligand 1 (PDL1). Over-expression of lymphangiogenic genes including VEGFC was linked to increased disease-free and overall survival in patients with non-metastatic tumors, whereas its over-expression correlated with decreased progression-free and overall survival of metastatic patients.Conclusion: Our study revisited the admitted dogma linking VEGFC to tumor aggressiveness. We conclude that targeting VEGFC for therapy must be considered with caution.

Adverse Effect of Lymph Node Dissection in Metastatic Renal Cell Cancer Patients Treated with Cytoreductive Nephrectomy: A Contemporary Analysis of Survival.

Background and objectives: In patients with metastatic renal cell cancer (mRCC), cytoreductive nephrectomy (CN) may occasionally be performed. However, the role of lymph node dissection (LND) for such cases is unknown in era of target therapy. To test the effect of LND at CN on cancer-specific survival (CSS), overall survival (OS) in era of target therapy compared with no LND in patients with mRCC.Methods: A total of 4690 mRCC patients treated with CN were identified within the Surveillance, Epidemiology, and End Result (SEER) database (2006-2015). Survival differences were assessed by Kaplan-Meier estimate and compared using log-rank test. Multivariable Cox regression analysis (MCR) was used to evaluate the effect of LND on CSS and OS.Results: Within the SEER database, 1902 (40.6%) of 4690 mRCC patients underwent LND at CN. MCR analysis showed that LND at CN exhibited lower CSS (hazard ratio [HR] 1.18, 95% confidence interval (CI) 1.09-1.27; p < 0.01) and OS (HR 1.13, 95% CI 1.05-1.21; p < 0.01) compared with non-LND in mRCC patients. The adverse effect of LND on CSS and OS were also detected in metastatic patients with clear cell RCC (ccRCC) and non-ccRCC (all p<0.0001). Additionally, the association of number of resected node with CSS (HR 0.98, 95% CI 0.88-1.10; p = 0.68) and OS (HR 1.00, 95% CI 0.89-1.11; p = 0.93) were not observed in MCR analysis.Conclusion: We are the first to demonstrate that LND at CN is associated with poor CSS and OS in metastatic patients with ccRCC and non-ccRCC. Considering that the current study is retrospective, these findings' impact on clinical practice needs to be further verified in future validation studies.

Long-term survival improvement in oesophageal cancer in the Netherlands

BackgroundTreatment for oesophageal cancer has evolved due to developments including the centralisation of surgery and introduction of neoadjuvant treatment. Therefore, this study evaluated trends in stage distribution, treatment and survival of oesophageal cancer patients in the last 26 years in the Netherlands. Patients and methodsPatients with oesophageal cancer diagnosed in the period 1989–2014 were selected from the Netherlands Cancer Registry. Patients were divided into two groups: non-metastatic (M0) and metastatic (M1). Trends in stage distribution, treatment and relative survival rates were evaluated according to histology. ResultsAmong all 35,760 patients, the percentage of an unknown tumour stage decreased from 34% to 10% during the study period, whereas the percentage of patients with metastatic disease increased from 21% to 34%. Among surgically treated patients 32% underwent a resection in a high-volume hospital in 2005 which increased to 92% in 2014. Use of neoadjuvant chemoradiotherapy increased in non-metastatic oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC) patients from respectively 4% and 2% in 2000–2004 to 43% and 26% in 2010–2014. Five-year relative survival increased from 8% to 22% for all patients; from 12% to 36% for non-metastatic OAC and from 9% to 27% for non-metastatic OSCC over 26 years. Median overall survival of metastatic patients improved from 18 to 22 weeks. ConclusionIn the Netherlands, survival for oesophageal cancer patients improved significantly, especially in the period 2005–2014 which might be the result of better treatment related to the centralisation of surgery and introduction of neoadjuvant chemoradiotherapy.

A Comparison of Three Methods for the Detection of Circulating Tumor Cells in Patients with Early and Metastatic Breast Cancer

Background: We directly compared CTC detection rates and prognostic significance, using three different methods in patients with breast cancer (BC). Methods: Early (n=200) and metastatic (n=164) patients were evaluated before initiating adjuvant or first-line chemotherapy, using the CellSearch^TM System, an RT-qPCR for CK-19 mRNA detection and by double immunofluorescence (IF) microscopy using A45-B/B3 and CD45 antibodies. Results: Using the CellSearch^TM System, 37% and 16.5% of early BC patients were CTC-positive (at ≥1 and ≥2 CTCs/23 ml of blood), 18.0% by RT-qPCR and 16.9% by IF; no agreement was observed between methods. By the CellSearch^TM 34.8% and 53.7% (at≥ 5 and ≥ 2 CTCs/7.5 ml) of metastatic patients were CTC-positive, 37.8% by RT-qPCR and 28.5% by IF. A significant agreement existed only between the CellSearch^TM and RT-qPCR. In 60.8% of cases, differential EpCAM and CK-19 expression on CTCs by IF could explain the discrepancies between the CellSearch^TM and RT-qPCR. CTC-positivity by either method was associated with decreased overall survival in metastatic patients. Conclusion: A significant concordance was observed between the CellSearch^TM and RT-qPCR in metastatic but not in early BC. Discordant results could be explained in part by CTC heterogeneity. CTC detection by all methods evaluated had prognostic relevance in metastatic patients.

Abstract 3423: Overweight and obesity predict better overall survival rates in cancer patients with distant metastases

Abstract Background: Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status. Methods: Between 2000 and 2012, a total of 4,010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis. Results: The median OS time was 3.23 months (range: 0.1−122.17) for underweight patients, 6.08 months (range: 0.03−149.46) for normal-weight patients, 7.99 months (range: 0.07−158.01) for overweight patients, and 12.49 months (range, 0.2−164.1) for obese patients (log-rank: P &amp;lt; 0.001). Compared with normal-weight patients, both obese (HR = 0.676; 95% P &amp;lt; 0.001) and overweight individuals (HR = 0.84; P &amp;lt; 0.001) had a reduced risk of all-cause mortality in multivariable analysis. Conversely, underweight patients had a significantly higher risk of death from all causes (HR = 1.41; P &amp;lt; 0.001). Conclusions: Overweight and obesity are independent predictors of better OS in metastatic patients with a good performance status. Increased BMI may play a role to identify metastatic patients with superior survival outcome and exhibit a potential to encourage aggressive management in those patients even with metastases. Citation Format: Ngan M. Tsang. Overweight and obesity predict better overall survival rates in cancer patients with distant metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3423.

Overweight and obesity predict better overall survival rates in cancer patients with distant metastases

Recent studies conducted in patients with chronic diseases have reported an inverse association between body mass index (BMI) and mortality. However, the question as to whether BMI may predict prognosis in patients with metastatic cancer remains open. We therefore designed the current retrospective study to investigate the potential association between BMI and overall survival (OS) in patients with distant metastases (DM) and a favorable performance status. Between 2000 and 2012, a total of 4010 cancer patients with DM who required radiotherapy (RT) and had their BMI measured at the initiation of RT were identified. The relation between BMI and OS was examined by univariate and multivariable analysis. The median OS time was 3.23 months (range: 0.1–122.17) for underweight patients, 6.08 months (range: 0.03–149.46) for normal‐weight patients, 7.99 months (range: 0.07–158.01) for overweight patients, and 12.49 months (range, 0.2–164.1) for obese patients (log‐rank: P < 0.001). Compared with normal‐weight patients, both obese (HR = 0.676; 95% P < 0.001) and overweight individuals (HR = 0.84; P < 0.001) had a reduced risk of all‐cause mortality in multivariable analysis. Conversely, underweight patients had a significantly higher risk of death from all causes (HR = 1.41; P < 0.001). Overweight and obesity are independent predictors of better OS in metastatic patients with a good performance status. Increased BMI may play a role to identify metastatic patients with superior survival outcome and exhibit a potential to encourage aggressive management in those patients even with metastases.

Expression of truncated human epidermal growth factor receptor 2 on circulating tumor cells of breast cancer patients.

IntroductionThe truncated form of human epidermal growth factor receptor 2 (p95HER2) lacks the HER2 extracellular domain and has been associated with poor prognosis and resistance to trastuzumab. In the present study, the expression of p95HER2 was investigated on circulating tumor cells (CTCs) from breast cancer patients.MethodsTriple-staining immunofluorescent experiments were performed on peripheral blood mononuclear cells’ (PBMCs) cytospins obtained from patients with early (n = 24) and metastatic (n = 37) breast cancer. Cells were stained with the pancytokeratin (A45-B/B3) antibody coupled with antibodies against the extracellular (ECD) and the intracellular (ICD) domains of HER2. Slides were analyzed with either confocal laser scanning microscopy or with the Ariol system.ResultsHER2-positive CTCs were identified in 55.6 % of early and 65.2 % of metastatic CTC-positive breast cancer patients. p95HER2-positive CTCs were identified in 11.1 % of early and 39.1 % of metastatic breast cancer patients (p = 0.047). In 14 patients with metastatic HER2-positive breast cancer, CTCs were also analyzed before and after first-line trastuzumab therapy. Trastuzumab reduced the percentage of patients with full-length HER2-positive CTCs from 70 % at baseline to 50 % (p = 0.035) after treatment while increased the percentage of patients with p95HER2-positive CTCs from 40 % to 63 %. Moreover, the overall survival of metastatic patients with p95HER2-positive CTCs was significantly decreased (p = 0.03).Conclusionsp95HER2-positive CTCs can be detected in both early and metastatic breast cancer patients. Their incidence is increased in the metastatic setting and their presence is associated with poor survival. Longitudinal studies during anti-HER2 treatment are required to determine the clinical relevance of p95HER2-expressing CTCs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0624-x) contains supplementary material, which is available to authorized users.