Primary Tumor Status Research Articles

Adjuvant Chemotherapy Treatment after Radical Cystectomy in Patients with Muscle Invasive Bladder Cancer

Background: about 25% of patients newly diagnosed with bladder cancer have muscle-invasive bladder cancer (MIBC). Patients with MIBC have a worse prognosis than those with non-MIBC. Radical cystectomy with pelvic lymphadenectomy has been shown to be effective against MIBC. The pathologic stage of the primary tumor and regional lymph nodes status has been shown to be the most accurate predictors of disease recurrence after radical cystectomy. Aim of the Work: to evaluate the toxicity profile related to the adjuvant chemotherapy cisplatin, gemcitabine when added to radical cystectomy as primary treatment, and to estimate disease free survival (DFS) and overall survival (OS). Patients and Methods: during the period between December 2013 and October, 2017, a total number of 42 patients were included in this study at Clinical Oncology and Nuclear Medicine Department, Al-Hussein University Hospital with a provisional diagnosis of invasive type bladder cancer. The cutoff date for the analysis of overall survival was 31st April, 2018 corresponding to 6 months of follow-up for the last patient enrolled in the study. All patients were subjected to radical cystectomy and pelvic lymphadenectomy and received four cycles of adjuvant chemotherapy cisplatin 70mg/m2 D1, gemcitabine 1000mg/m2 D1,8, every three weeks. Results: the most common grade 3 and 4 adverse events of hematological and non-hematological toxicities recorded during adjuvant chemotherapy were neutropenia (18.8%), grade 3 anemia (9.5%), grade 3 thrombocytopenia (2.3%), grade 3 nausea (28.5%), grade 3 and 4 vomiting (9.4%), grade 3 diarrhea (9.4%) while grade 3 renal toxicities observed in two patients (4.7%). As regard the survival analysis, the median disease-free survival (DFS) rate was not reached due to a relatively short follow up period and DFS was 82.9% at 1 year, 74% at 2 years, and 70.1% at 3 years. Concerning overall survival analysis, the median overall survival in our study was not reached due to a relatively short follow up period. Overall Survival rate at 1 year was 90.4%; at 2 years was 77.3% and 73.4% at 3 years. Conclusion: for patients with bladder cancer who were not treated with neoadjuvant chemotherapy, we suggest not routinely administering chemotherapy following cystectomy. However, for patients with high-risk (T3 or higher, pathologic node involvement) urothelial carcinomas who are candidates for cisplatin -based combination chemotherapy and are willing to accept the risk for treatment-related toxicities in the absence of high level of evidence, adjuvant chemotherapy is a reasonable option. If administered, we prefer to use a cisplatin-based combination.

Prognostic effect of factors involved in revised Tokuhashi score system for patients with spinal metastases: a systematic review and Meta-analysis

BackgroundCancer patients’ survival time has obviously improved, with the development of systemic treatment techniques. However, the probability of metastases to the vertebrae has also been increased which makes some adverse effects on patients’ quality of life. The prediction of survival plays a key role in choosing therapeutic modality, and Tokuhashi Score was established as one of the most commonly used predictive systems for spinal metastases. Thus, this study was conducted to identify the prognostic effect of factors involved in revised Tokuhashi Score (RTS).MethodsTwo investigators independently retrieved relevant literature on platforms of PubMed, Embase and Cochrane Library. We identified eligible studies through title/abstract and full-text perusing. Data was extracted including general information of studies, participants’ characteristics, therapeutic modality, overall survival and prognostic effect of factors. Hazard ratio (HR) for each factor was synthesized if available through fixed- or random-effect models as appropriate.ResultsA total of 63 eligible studies with 10,411 participants were identified. Overall, cases with thyroid cancer had the highest survival rate, while the ones with non-small cell lung cancer and hepatocellular carcinoma lived for the shorted survival time. Performance status, bone metastasis, number of involved vertebrae, visceral metastasis, primary tumor and neurological status were regarded as significant predictors in 71.4, 40.0, 18.2, 63.4, 73.1 and 44.7% of the involved studies respectively. Thirty-eight articles were included in meta-analysis, and prognostic effects of five factors (apart from primary tumor) were analyzed. Factors were all proved to be significant except comparisons between KPS (Karnofsky Performance Status) 10–40 VS. 50–70 and single VS. multiple spinal metastases.ConclusionAll factors of RTS were significant on prognosis predicting and should be considered when choosing therapeutic modality for spinal metastases. What’s more, we believe that more accurate prognosis may be obtained after removal of the cut-offs for KPS 10–40 VS. 50–70 and single VS. multiple involved vertebrae.

Epidermal Growth Factor Receptor Mutation Detection in Cerebrospinal Fluid of Lung Adenocarcinoma Patients with Leptomeningeal Metastasis.

Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative. To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM. Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded. Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion. EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments.

Mutational profile of colorectal cancer lung metastases and paired primary tumors by targeted next generation sequencing: implications on clinical outcome after surgery.

Pulmonary metastasectomy is one of the cornerstones in the treatment of oligometastatic colorectal cancer (CRC). However, the selection of patients who benefit from a surgical resection is difficult. Mutational profiling has become an essential part of diagnosis and treatment of malignant disease. Despite this, comprehensive data on the mutational profile of CRC and its clinical impact in the context of pulmonary metastasectomy is sparse. We therefore aimed to provide a complete mutational status of CRC pulmonary metastases (PM) and corresponding primary tumors by targeted next-generation sequencing (tNGS), and correlate sequencing data with clinical outcome variables. Case-matched, formalin-fixed paraffin embedded surgical specimens of lung metastases (n=47) and matched primary CRC (n=24) were sequenced using the TruSeq Amplicon Cancer Panel (Illumina platform). Penalized Cox regression models were applied to identify mutations with prognostic impact. Mutations were found most frequently in APC, TP53 and KRAS, in both PM and matched primary tumors. Concordance between primary tumors and PM was 83.5%. Adaptive elastic-net regularized Cox regression models identified mutations being prognostic for time to pulmonary recurrence (EGFR, GNAQ, KIT, MET, and PTPN11) and for overall survival (OS) (PDGFRA, SMARCB1, and TP53). Our findings suggest that CRC PM harbor a variety of conserved and de novo mutations. We could identify a mutational profile predicting clinical outcome after pulmonary metastasectomy. Moreover, our data provide a rationale for future targeted therapies of patients with CRC lung metastases.

Margin status and long-term prognosis of primary pancreatic neuroendocrine tumor after curative resection: Results from the US Neuroendocrine Tumor Study Group

BackgroundThe impact of margin status on resection of primary pancreatic neuroendocrine tumors has been poorly defined. The objectives of the present study were to determine the impact of margin status on long-term survival of patients with pancreatic neuroendocrine tumors after curative resection and evaluate the impact of reresection to obtain a microscopically negative margin. MethodsPatients who underwent curative-intent resection for pancreatic neuroendocrine tumors between 2000 and 2016 were identified at 8 hepatobiliary centers. Overall and recurrence-free survival were analyzed relative to surgical margin status using univariable and multivariable analyses. ResultsAmong 1,020 patients, 866 (84.9%) had an R0 (>1 mm margin) resection, whereas 154 (15.1%) had an R1 (≤1 mm margin) resection. R1 resection was associated with a worse recurrence-free survival (10-year recurrence-free survival, R1 47.3% vs R0 62.8%, hazard ratio 1.8, 95% confidence interval 1.2–2.7, P = .002); residual tumor at either the transection margin (R1t) or the mobilization margin (R1m) was associated with increased recurrence versus R0 (R1t versus R0: hazard ratio 1.8, 95% confidence interval 1.0–3.0, P = .033; R1m versus R0: hazard ratio 1.3, 95% confidence interval 1.0–1.7, P = .060). In contrast, margin status was not associated with overall survival (10-year overall survival, R1 71.1% vs R0 71.8%, P = .392). Intraoperatively, 539 (53.6%) patients had frozen section evaluation of the surgical margin; 49 (9.1%) patients had a positive margin on frozen section analysis; 38 of the 49 patients (77.6%) had reresection, and a final R0 (secondary R0) margin was achieved in 30 patients (78.9%). Extending resection to achieve an R0 status remained associated with worse overall survival (hazard ratio 3.1, 95% confidence interval 1.6–6.2, P = .001) and recurrence-free survival (hazard ratio 2.6, 95% confidence interval 1.4–5.0, P = .004) compared with primary R0 resection. On multivariable analyses, tumor-specific factors, such as cellular differentiation, perineural invasion, Ki-67 index, and major vascular invasion, rather than surgical margin, were associated with long-term outcomes. ConclusionMargin status was not associated with long-term survival. The reresection of an initially positive surgical margin to achieve a negative margin did not improve the outcome of patients with pancreatic neuroendocrine tumors. Parenchymal-sparing pancreatic procedures for pancreatic neuroendocrine tumors may be appropriate when feasible.

Prognostic and risk factors in patients with metastatic bone disease of an upper extremity

BackgroundThe aim of this study was to evaluate survival of metastatic bone disease of an upper extremity, and to identify the prognostic factors that influence survival. MethodsPatients with metastatic bone disease of an upper extremity between 2008 and 2015 were reviewed from the database of a tertiary university hospital. ResultsOf 102 patients, 48 males and 54 females with a median age of 61 (range, 28–82 years), the humerus (64.7%), clavicle (13.7%), and scapula (12.7%) were the common sites for bone metastasis of an upper extremity. Fifty-nine (57.8%) presented with pathologic fracture. No history of cancer was found in 76.5% of patients. The mean onset of metastatic bone disease after the first diagnosis of primary cancer was 4.74 ± 14.07 months (range, 0–84 months). Lung (31.4%) was the most common primary cancer followed by liver (14.7%), breast (12.7%), thyroid (7.8%), and renal (3.9%). Eighty-two cases (80.39%) died from the disease such that the median survival was 4.08 months (95% CI 2.57–6.17). The significant risk factors were the type of primary tumor (P < 0.001, HR = 4.44; 95% CI, 1.99–9.90) and ECOG performance status (P = 0.021, HR = 2.11, 95% CI 1.12–3.99). ConclusionsPatients with metastatic bone disease of an upper extremity have a limited life expectancy. The type of primary tumor and ECOG performance status were the important prognostic factors that influenced overall survival. Our data help in the management of patients, families, and doctors, so as to avoid over- or under-treatment.

Abstract 2217: Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review

Abstract Introduction: This systematic literature review sought to determine the concordance of PIK3CA mutations in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients. Methods: A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts was performed by two independent researchers that included, but was not limited to, keywords: “breast neoplasm,” “PIK3CA protein,” “hormone receptor positive,” and “metastases.” Databases were searched for English-language publications in HR+, HER2- mBC published between January 1993 through August 2017. Studies were included if results reported were specific to patients with HR+, HER2- mBC and reported data comparing PIK3CA mutations from liquid biopsies versus tumor biopsies or primary tumor samples versus metastatic lesion samples. Concordance was assessed between tissue samples (mutations found in primary tumors versus those from metastatic lesions) and between biopsy methods (i.e., tumor biopsy versus liquid biopsy) when the assessment was done at a variety of time points including time of initial diagnosis and time of diagnosis at disease progression. Content analysis was employed to quantify collected data elements. Results: Of 558 studies included for full-text review, four met inclusion criteria (number of patient samples [n]=358). One study (n = 9) found the concordance between the mutation status of primary breast tumors to the mutation status of metastatic lesions to be 100%. Three studies (n = 47; n = 55; n = 247) determined the concordance of PIK3CA mutations between tumor biopsies and liquid biopsies with concordance ranging from 70.4% to 94%. One study found that the concordance of circulating tumor DNA (ctDNA) against tumor biopsy was higher among metastatic lesions only (81.6%) relative to using all tumor samples (either primary or metastatic lesions) (70.4%). Conclusions: Available evidence suggested high level of concordance across sampling methods as well as across time. However, additional evidence is needed to increase study generalizability as well as to assess other possible confounding factors, such as differential timing between tumor and liquid biopsies. Citation Format: Alejandra Aguilar, Joni Dean, Elizabeth Anderson, Lea Mollon, Lisa Davis, Terri Warholak, Ayal Aizer, Emma Platt, Aditya Bardiya, Derek Tang. Concordance of PIK3CA mutations in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer: A systematic literature review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2217.

Abstract 942: Sensitive detection of microsatellite instability (MSI) in tumors and liquid biopsies using nuclease-based enrichment

Abstract The role of MSI in colorectal cancer (CRC) is well characterized, and colon tumors are classified as MSI-High or MSI-Stable by screening specific microsatellites. MSI-H compared to MSI-S is predictive for therapy outcome in chemotherapy and immunotherapy and has been associated with distinct characteristics and favorable results including better prognosis, a higher 5-year survival, and lesser metastasis. Several other tumors also present MSI changes reflecting mismatch repair deficiency. While tumor testing is the gold standard, a convenient approach to screen for MSI before and during cancer treatment is screening circulating DNA (liquid biopsy) using a blood draw, thereby interrogating ‘systemic' MSI reflecting primary or secondary (occult) tumor status at the time of blood collection. However, presence of excess unaltered, wild-type DNA often masks alterations such as MSI. Using capillary electrophoresis or next generation sequencing for MSI detection presents challenges at low levels of MSI due to polymerase slippage (‘stutter') that generate high false positive rates at positions of homo-polymers. We present a new approach for enrichment of altered micro-satellites prior to DNA-amplification thereby facilitating their detection. We recently developed nuclease-assisted minor-allele enrichment with probe-overlap, a single-step approach that removes WT-DNA and enriches mutation-containing alleles. Here we adapted NaME-PrO for detection of homopolymer indels, for MSI detection. The method employs a double-strand-DNA-specific nuclease and overlapping oligonucleotide-probes interrogating multiple micro-satellite targets. Following DNA denaturation, the probes form double-stranded regions with their targets, thereby guiding nuclease digestion to selected sites. Microsatellite indels create ‘bulges' that inhibit digestion, thus subsequent amplification yields DNA with microsatellite alterations enhanced at multiple targets. The assay is applied at the genomic or circulating-DNA level prior to amplification, thereby avoiding polymerase-introduced ‘stutter peaks' arising from WT DNA. Inclusion of organic solvents allows homogeneous application of the method in closed tube reactions. We validated the method by evaluating 5 MSI targets simultaneously, NR27, NR21, NR24, BAT25 and BAT26 using DNA from tumor biopsies and circulating-DNA from colorectal cancer patients. The technique enriched all altered targets and detected microsatellite alterations down to 0.01% altered allele frequency, thus improving detection sensitivity by &amp;gt;100-fold relative to current approaches. We anticipate application of this highly- multiplex-able method either with standard 5-plex reactions in conjunction with capillary electrophoresis or with NGS-based detection of MSI on thousands of targets to enable sensitive detection in tumors and liquid biopsies. Citation Format: Ioannis Ladas, Chen Song, Fangyan Yu, Ka Wai Leong, Katerina Troullinou, Matthew Kulke, Harvey Mamon, Mike G. Makrigiorgos. Sensitive detection of microsatellite instability (MSI) in tumors and liquid biopsies using nuclease-based enrichment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 942.

Abstract 652: Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis: Comparison of primary thyroid cancer and metastatic lymph nodes

Abstract Introduction: Papillary thyroid microcarcinoma (PTMC) has excellent clinical outcomes, but distant metastasis of PTMC can be fatal. We previously reported that change to an aggressive pathologic subtype of metastatic lymph nodes (LNs) were associated with distant metastasis of PTMC. This study aimed to evaluate and compare the mutational profile of primary tumor and metastatic LNs of PTMC. Method: We included 16 PTMC patients with lateral cervical LN metastases. One of them has distant metastases. DNAs from formalin-fixed, paraffin-embedded archival samples of 16 sets of the normal thyroid tissue, primary PTMC, and the largest metastatic LN were used for targeted next-generation sequencing by Oncopanel AMC version 2.0. Results: A total of 7 somatic variants were confirmed in primary PTMC compared to normal thyroid tissue. BRAF V600E mutation was the most common and seen in 12 primary PTMCs (75%) and 11 metastatic LNs (69%). Missense mutation of KMT2A, RAF1, and ROS1 was detected only in one primary PTMC (6.3%), respectively. Frame-shift mutation of JAK2, inframe deletion of ACVR2A and nonsense mutation of AR was detected one primary PTMC (6.3%) with its metastatic LN, respectively. When we compare the mutational profile of primary tumor and metastatic LNs, there were no newly developed somatic mutations in metastatic LNs. We also found ALK/STRN rearrangement in one PTMC with its metastatic LN (6.3%). CCDC6/RET rearrangement and RET intergenic rearrangement was detected only in 2 metastatic LNs (12.5%) and one metastatic LN (6.3%), respectively. BARD1 deletion was detected in one primary PTMC with its metastatic LNS (6.3%) and FLT4 deletion was detected only in one primary PTMC (6.3%). We also found JAK1, AURKC, and TP53 deletions, which were detected only in one metastatic LN, respectively (6.3%). Conclusion: The mutation frequency of PTMC was really low even in patients with extensive LN metastasis. The mutational status of primary tumor and their regional metastatic LNs were not significantly different and this suggests the minor role of genetic mutations in the process of LN metastases. Citation Format: Min Ji Jeon, Won Gu Kim, Sung Min Chun, Dong Eun Song, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis: Comparison of primary thyroid cancer and metastatic lymph nodes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 652.

Anterior Approach to Major Resection for Colorectal Liver Metastasis

PurposeThe aim of this study was to examine the merits of the anterior approach, if any, in colorectal liver metastasis (CRLM) resection. MethodsData of patients who underwent partial hepatectomy for CRLM were reviewed. Patients treated by the anterior approach were compared with patients treated by the conventional approach. ResultsNinety-eight patients had right hepatectomy, extended right hepatectomy, or right trisectionectomy. Among them, 71 patients underwent the conventional approach (CA group) and 27 underwent the anterior approach (AA group). The two groups were comparable in demographic, pathological, and perioperative characteristics except that the AA group had higher levels of aspartate transaminase (median, 41 vs. 31 U/L; p = 0.006) and alanine transaminase (median, 27 vs. 22 U/L; p = 0.009), larger tumors (median, 7 vs. 4 cm; p = 0.000), and more extensive resections (p < 0.001). The median overall survival was 40 months (range, 0.69–168.6 months) in the CA group and 33.7 months (range, 0.95–99.8 months) in the AA group (p = 0.22), and the median disease-free survival was 9.7 months (range, 0.62–168.6 months) in the CA group and 6.2 months (range, 0.72–99.8 months) in the AA group (p = 0.464). Univariate and multivariate analyses identified 4 independent prognostic factors for overall survival: lymph node status of primary tumor (HR 1.352, 95% CI 0.639–2.862, p = 0.034), intraoperative blood loss (HR 1.253, 95% CI 1.039–1.510, p = 0.018), multiple liver tumor nodules (HR 1.775, 95% CI 1.029–3.061, p = 0.039), and microvascular invasion (HR 2.058, 95% CI 1.053–4.024, p = 0.035). ConclusionsThe two approaches resulted in comparable survival outcomes even though the AA group had larger tumors and more extensive resections. The anterior approach allows better mobilization and easier removal of large tumors once the liver is opened up.

Risk Factors and Adequate Management for Complications of Bevacizumab Treatment Requiring Surgical Intervention in Patients With Metastatic Colorectal Cancer

BackgroundBevacizumab (BV) has been approved for treating colorectal cancer since 2004. Although BV use may lead to adverse effects, few studies have reported incidences requiring surgical intervention. We aimed to identify the risk factors and adequate interventions for complications requiring surgical intervention after BV treatment. Patients and MethodsWe retrospectively reviewed the records of patients with metastatic colorectal cancer treated with BV in our institute from January 2009 to December 2016. The baseline patient characteristics were used to evaluate the potential risk factors for complications requiring surgery. ResultsOf the 1008 patients recruited for this study, 60 (5.9%) experienced complications necessitating surgery after BV therapy. Gastrointestinal perforation was the most frequently observed complication, occurring in 36 patients (3.5%), and diverting colostomy was the most commonly performed intervention (22 patients, 36.6%). Multivariate analysis helped identify poor differentiation, signet ring cell carcinoma, stent insertion status, rectal location of the primary tumor, and intact primary tumor status as the risk factors. Survival time remained unchanged regardless of a complication that required surgery. ConclusionCareful monitoring during BV treatment for metastatic colorectal cancer is essential for patients who have a predisposition to complications that may require surgery. After detection, adequate and timely surgical management is imperative for ensuring patient survival.

Feasibility of using negative ultrasonography results of axillary lymph nodes to predict sentinel lymph node metastasis in breast cancer patients.

Knowledge of the pathology of axillary lymph nodes (ALN) in breast cancer patients is critical for determining their treatment. Ultrasound is the best noninvasive evaluation for the ALN status. However, the correlation between negative ultrasound results and the sentinel lymph nodes (SLN) pathology remains unknown. To test the hypothesis that negative ultrasound results of ALN predict the negative pathology results of SLN in breast cancer patients, we assessed the association between ALN ultrasonography‐negative results and the SLN pathology in 3115 patients with breast cancer recruited between October 2010 and April 2016 from a single cancer center, prospective database. Of these patients who met the inclusion criteria, 2317 (74.4%) had no SLN pathological metastasis. In the univariate analysis, other 798 patient with positive SLN tended to be under age 40 and premenopausal, having large tumor sizes (>2 cm), higher histological grade of primary tumor, positive hormone receptors, and negative HER‐2 status (P < .05 for all). In the multivariate analysis, menstrual status, tumor size, ER status and histological types of primary tumor remained to be independent predictors for SLN pathological metastasis. The area under curve (AUC) was 0.658 (95% CI = 0.637‐0.679), P > .05. In conclusion, only a 74.4% consistency between ALN ultrasonography‐negative results and negative pathological SLN results, although menstrual status, tumor size, histologic subtypes of primary tumor and ER status were found to be statistically independent predictors of positive SLN among patients negative for ALN ultrasonography. Therefore, the present study suggests that negative ultrasound results of ALN do not adequately predict the negative pathology results of SLN in breast cancer patients.

ESR1 methylation in primary tumors and paired circulating tumor DNA of patients with high-grade serous ovarian cancer

ObjectiveEstrogen receptor, coded by the ESR1 gene, is highly expressed in epithelial ovarian cancer. ESR1 gene is frequently methylated in many types of gynecological malignancies. However, only a few studies attempted to investigate the role of ESR1 methylation and its clinical significance in ovarian cancer so far. The aim of our study was to examine ESR1 methylation status in primary tumors and corresponding circulating tumor DNA of patients with high-grade serous ovarian cancer (HGSC). MethodsESR1 methylation was detected by a highly specific and sensitive real-time methylation-specific PCR assay. Two groups of HGSC samples were analyzed: group A (n = 66 primary tumors) and group B (n = 53 primary tumors and 50 corresponding plasma samples). ResultsESR1 was found methylated in both groups of primary tumors: in 32/66 (48.5%) of group A and in 15/53 (28.3%) of group B. 19/50 (38.0%) corresponding plasma samples of group B were also methylated for ESR1. A significant agreement for ESR1 methylation was observed between primary tumors and paired plasma ctDNA samples (P = 0.004). Interestingly, the presence of ESR1 methylation in primary tumor samples of group B was significantly correlated with a better overall survival (P = 0.027) and progression-free survival (P = 0.041). ConclusionsWe report for the first time the presence of ESR1 methylation in plasma ctDNA of patients with HGSC. The agreement between ESR1 methylation in primary tumors and paired ctDNA is statistically significant. Our results indicate a correlation between the presence of ESR1 methylation and a better clinical outcome in HGSC patients.

Companied P16 genetic and protein status together providing useful information on the clinical outcome of urinary bladder cancer.

SPEC P16/CEN3/7/17 Probe fluorescence-in-situ-hybridization (FISH) has become the most sensitive method in indentifying the urothelial tumors and loss of P16 has often been identified in low-grade urothelial lesions; however, little is known about the significations of other P16 genetic status (normal and amplification) in bladder cancer.We detected P16 gene status by FISH in 259 urine samples and divided these samples into 3 groups: 1, normal P16; 2, loss of P16; and 3, amplified P16. Meanwhile, p16INK4a protein expression was measured by immunocytochemistry and we characterized the clinicopathologic features of cases with P16 gene status.Loss of P16 occurred in 26.2%, P16 amplification occurred in 41.3% and P16 gene normal occurred in 32.4% of all cases. P16 genetic status was significantly associated with tumor grade and primary tumor status (P = .008 and .017), but not with pathological tumor stage, overall survival, and p16 protein expression. However, P16 gene amplification accompanied protein high-expression has shorter overall survival compared with the overall patients (P = .023), and P16 gene loss accompanied loss of protein also had the tendency to predict bad prognosis (P = .067).Studies show that the genetic status of P16 has a close relation with the stages of bladder cancer. Loss of P16 is associated with low-grade urothelial malignancy while amplified P16 donotes high-grade. Neither P16 gene status nor p16INK4a protein expression alone is an independent predictor of urothelial bladder carcinoma, but combine gene and protein status together providing useful information on the clinical outcome of these patients.

Androgen receptor in advanced breast cancer: is it useful to predict the efficacy of anti-estrogen therapy?

BackgroundAndrogen receptor (AR) is widely expressed in breast cancer (BC) but its role in estrogen receptor (ER)-positive tumors is still controversial. The AR/ER ratio has been reported to impact prognosis and response to antiestrogen endocrine therapy (ET).MethodsWe assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced BC. Patients who had received first-line ET (2002–2011) were recruited, while those given concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy were excluded. ER, progesterone receptor (PgR), Ki67 and AR expression were assessed by immunohistochemistry, and HER2 mainly by fluorescent in-situ hybridization. Cut-offs of 1 and 10% immunostained cells were used to categorize AR expression.ResultsAmong 102 evaluable patients, biomarkers were assessed in primary tumors in 70 cases and in metastases in 49, with 17 patients having both determinations. The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR status. AR status did not affect TTP significantly, whereas PgR and Ki67 status did. AR/PgR ≥0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.028). AR status in primary tumors or metastases was not associated with progressive disease (PD) as best response. In contrast, Ki67 ≥ 20% and PgR < 10% showed a statistically significant association with PD as best response.ConclusionsAR expression does not appear to be useful to predict the efficacy of ET in advanced BC, whereas Ki67 and PgR exert a greater impact on its efficacy.

Surgery for brain metastases: An analysis of outcomes and factors affecting survival

ObjectivesFor patients who develop brain metastases from solid tumors, age, KPS, primary tumor status and presence of extracranial metastases have been identified as prognostic factors. However, the factors that affect survival in patients who are deemed fit to undergo resection of brain metastases have not been clearly elucidated hitherto. Patients and MethodsThis is a retrospective analysis of a prospectively maintained database. All patients who underwent resection of intracranial metastases from solid tumors were included. Various patient, disease and treatment related factors were analyzed to assess their impact on survival. ResultsOverall, 124 patients had undergone surgery for brain metastases from various primary sites. The median age and pre-operative performance score were 53 years and 80 respectively. Synchronous metastases were resected in 17.7% of the patients. The postoperative morbidity and mortality rates were 17.7% and 2.4% respectively. Adjuvant whole brain radiation was received by 64 patients. At last follow-up, 8.1% of patients had fresh post-surgical neurologic deficits. The median progression free and overall survival were 6.91 was 8.56 months respectively. ConclusionsSurgical resection of for brain metastases should be considered in carefully selected patients. Gross total resection and receiving adjuvant whole brain RT significantly improves survival in these patients.

Clinical assessment of cervical node in head and neck malignancy: case series

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Lymph node involvement is well established as an important prognostic factor for head and neck cancer, the spread of carcinoma of head and malignancy to the node levels is probably predictable according to the site of the primary. The appropriate staging of cervical lymph nodes is very important in the management of any head and neck primary carcinoma. Clinical palpation of cervical lymph nodes may yield false negative and false positive results. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;In a prospective study in patients of patients with primary malignancy from larynx, any sub site of pharynx (nasopharynx/oropharynx/hypopharynx) of histologically proven squamous cell carcinoma, the nodal status of primary tumour, the level of lymph node involved and the stage of presentation of the tumor and node were analysed clinically. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;61 cases included in our study, where males were 52 cases and females were 9 cases. The age incidence ranging from 35 years to 76 years noted&lt;strong&gt;.&lt;/strong&gt; In the distribution of nodal secondary carcinoma of the nasopharynx was 100% nodal positive followed by hypopharynx, oropharynx, and larynx. 21% of patient presented in the N&lt;sub&gt;0&lt;/sub&gt; stage. The remaining 79% were node positive. In nodal secondary by size of primary most of the patients presented with T&lt;sub&gt;3&lt;/sub&gt; disease (52%) followed by T&lt;sub&gt;2&lt;/sub&gt; disease (26%), T&lt;sub&gt;1&lt;/sub&gt; disease (11%) and T&lt;sub&gt;4&lt;/sub&gt; disease (11%). &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;In malignancy of larynx, pharynx, lymph node assessment clinically is an important prognostic factor to determine the staging of tumour. The clinical evaluation may also have false negative, so radiological evaluation will further give a detailed assessment of the nodes for better treatment outcomes to reduce the overall mortality.&lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt; &lt;/p&gt;

Abstract P6-06-02: Functional homologous recombination REpair CAPacity (RECAP) test in metastatic breast cancer biopsies

Abstract Introduction Tumors of germline BRCA1/2 mutated carriers cannot repair DNA double strand breaks (DSB) due to homologous recombination deficiency (HRD), rendering them highly sensitive to Poly ADP Ribose Polymerase (PARP) inhibitors and DSB inducing chemotherapy. Although evidence is emerging that the use of these therapies could be extended beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. We have developed a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh primary breast cancer (BrC) tissue: the RECAP test. Here, we investigated feasibility of this test on small biopsies from metastatic BrC lesions. Methods Patients with advanced or recurrent BrC with easily accessible metastases were eligible. Patients with pulmonary or bone metastases were excluded due to risk of pneumothorax and technical issues with calcifications. Biopsies were collected in customized DMEM/F12 medium, irradiated with 5Gy and cultured for 2 hours. Final test outcomes were available within 1 week after the biopsy procedure. The primary endpoint was the proportion of patients with a successful test result defined as either less than 20% (i.e. HRD), 20-50% (i.e. HR intermediate), or more than 50% (i.e. HR proficient) of S/G2 phase cells showing RAD51 foci. Using a Simon 2-stage design (p0=60%, p1=80%, α=0.1, β=0.1), 38 patients were required. When at least 27 had a successful test result, we decided to further develop this test. Results 51 patients enrolled in the RECAP trial. Core needle biopsies were collected from liver (n=16), breast (n=4), lymph nodes (n=13) and other sites (n=6), as well as punch biopsies from skin metastases (n=5). In 6 cases a biopsy could not be obtained; 1 patient was excluded as the biopsy appeared to be a metastasis of a neuroendocrine tumor. Of 44 obtained biopsies, 42 biopsies contained tumor cells. Successful test results were obtained in 40 of the 42 metastatic biopsies (95%, CI 89-100%). The reason for the two unsuccessful tests, both derived from ER+/PR+/HER2-liver metastases, was absence of tumor cells in S-phase. Success of the test in biopsies was independent of BrC subtype (p=0.12), histological grade (p=0.65), receptor status (p=0.74), biopsy type (p=0.82) and metastatic site (p=0.78). We found that 25 metastatic lesions were HR proficient, 13 were HR deficient and 2 were HR intermediate. Germline BRCA testing showed mutations in 6/13 HRD lesions. Somatic and epigenetic analyses are ongoing. Conclusion In this study, we enhance the diagnostic potential and clinical applicability of the functional RECAP test by demonstrating novel feasibility on metastatic biopsies from BrC patients. Robustness of the test is shown, as its applicability extends from core needle biopsies from different metastatic sites to punch biopsies from skin metastases. Comparison of HRD status of primary versus metastatic tumors and among BrC subtypes will be presented at the conference. Citation Format: Meijer TG, Verkaik NS, Naipal KAT, van Deurzen CHM, Kanaar R, van Gent DC, Jager A. Functional homologous recombination REpair CAPacity (RECAP) test in metastatic breast cancer biopsies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-06-02.

Abstract P5-21-14: Long-term survival in HER2-positive metastatic breast cancer treated with first-line trastuzumab: Real-life results from the Curie ESME database

Abstract Background About 20% of breast cancer (BC) patients will develop distant metastases. HER2-positive (HER2+) disease is associated with poorer prognosis. However, outcome of HER2+ BC patients has dramatically improved since the use of trastuzumab. Although most HER2+ metastatic BC (MBC) patients will eventually develop progressive disease within one year of trastuzumab-based treatment, some are long-term responders (LTR). Few data on these patients are available. Methods The primary objective was to assess overall survival (OS) of HER2+ MBC patients treated with trastuzumab as 1st-line at the Institut Curie, based on institution-specific data included in the French Epidemiological Strategy and Medical Economics (ESME) program for MBC patients established in 2014 by Unicancer. Long-term responders (LTR) were defined as having a non-progressive disease for at least 2 years under 1st-line trastuzumab. Secondary objectives included progression-free survival (PFS), disease-free interval (DFI), prediction factors for LTR status by univariate and multivariate analysis: characteristics of patients (age, BMI, menopausal status), of primary tumour (e.g. hormone receptor (HR) status), of treatment (e.g. endocrine therapy, partner for trastuzumab combination), number and type of metastases. Results From 2008 to 2014, 2990 MBC patients were identified in the Curie-ESME MBC database. Of these, 460 had HER2+ disease. Sixteen patients with second primary malignancy were excluded. Of the 444 remaining patients, 340 received 1st-line trastuzumab and could be analyzed. With a 42.5-month median follow-up time, the mean age at metastatic diagnosis was 55.7 years, 59.4% had a HR-positive disease and 43.2% had de novo metastases or occurring within 6 months after adjuvant treatment. DFI was &amp;gt;24 months in 47.9% of patients, and 78.5% received 1st-line trastuzumab combined with taxane-based chemotherapy (CT). In 87 patients (25.6%) classified as LTR, median PFS was 56.2 months (CI95% 41.53-not reached) vs. 10.9 months in non-LTR (CI95% 9.46-11.8). Median OS in LTR is not reached versus 44.3 months in non-LTR (CI95% 37.9-49.1). Median age, menopausal status, BMI, pathological characteristics and treatment for primary BC were similar in both groups. The following factors were predictive of LTR status by univariate analysis: number of metastatic sites (&amp;lt;3 versus &amp;gt; 3, p=0.022); endocrine treatment for metastatic disease (p=0.002); absence of central nervous system metastases (p=0.035); and taxane-based 1st- line CT (p=0.032). In multivariate analysis, only number of metastatic sites and taxane-based 1st-line CT were predictive of LTR status. In contrast, age, DFI, visceral disease, and adjuvant trastuzumab-based treatment did not influence outcome. Although not statistically significant, HR+ status was more frequent in LTR versus non-LTR patients (66.7% versus 56.9%). Conclusions With a median follow-up of 42.5 months, we found that more than 95% of LTR to 1st-line trastuzumab were still alive and could achieve a median PFS longer than 4.6 years. Although some clinical factors are clearly associated with better outcome, further investigations are needed to identify the mechanisms of resistance or sensitivity to trastuzumab. Citation Format: Kaczmarek E, Saint-Martin C, Pierga J-Y, Brain E, Rouzier R, Dubot C, Savignoni A, Mouret-Fourme E, Simon G, Carton M, Lerebours F. Long-term survival in HER2-positive metastatic breast cancer treated with first-line trastuzumab: Real-life results from the Curie ESME database [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-14.

Solitary Pulmonary Lesion in Patients with History of Malignancy: Primary Lung Cancer or Metastatic Cancer?

Defining the status of solitary pulmonary lesion (SPL) in patients with history of malignancy is important because primary lung cancer (PLC) or intrapulmonary metastasis might indicate different surgical strategies. The aim of this study is to identify factors related to the status of these lesions and construct a clinical model to estimate the pretest probability of PLC. From January 2005 to January 2016, 104 patients with previous malignancy and suitable for surgery were retrospectively studied. Univariate and multivariate analyses were performed to identify possible factors related to SPLs. A nomogram was constructed to differentiate PLC from intrapulmonary metastasis. Ninety-seven (93.3%) patients were diagnosed as malignant postoperatively, including 61 patients with intrapulmonary metastasis and 36 patients with PLC. Multivariate analysis showed that site of primary tumor [head and neck squamous cell cancer: odds ratio (OR)=28.509, P=0.006; genitourinary cancer: OR=23.928, P=0.012], negative lymph node status of primary tumor (OR=3.154, P=0.038), spiculation of SPL (OR=3.972, P=0.022), and central location of SPL (OR=4.679, P=0.026) were four independent factors differentiating PLC from intrapulmonary metastasis. All of these were included in the nomogram. The C-index of the nomogram for predicting probability was 0.82. Incidence of malignant SPLs was fairly high in patients with history of malignancy. A nomogram including site and lymph node status of primary tumor, and spiculation and location of SPL might be a good tool for differentiating PLC from intrapulmonary metastasis preoperatively and guiding treatment.