Perioperative and palliative systemic treatments for biliary tract cancer.

Due to the fact biliary tract cancer (BTC) is often diagnosed at an advanced stage, thus, not eligible for resection, and due to the aggressive tumor biology, it is considered as one of the cancer types with the worst prognosis. Advances in diagnosis, surgical techniques, and molecular characterization have led to an improvement of the prognosis of BTC patients, recently. Although neoadjuvant therapy is expected to improve surgical outcomes by reducing tumor size, its routine is not well established. The application of neoadjuvant therapy in locally advanced disease may be indicated, the routine use of systemic therapy prior to surgery for cholangiocarcinoma patients with an upfront resectable disease is less well established, but discussed and performed in selected cases. In advanced disease, only combination chemotherapy regimens have been demonstrated to achieve disease control in untreated patients. Molecular profiling of the tumor has demonstrated that many BTC might bear actionable targets, which might be addressed by biological treatments, thus improving the prognosis of the patients. Furthermore, the addition of the immunotherapy to standard chemotherapy might improve the prognosis in a subset of patients. This review seeks to give a comprehensive overview about the role of neoadjuvant as well as palliative systemic treatment approaches and an outlook about novel systemic treatment concept in BTC.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment.

Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics-next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7-29.3) vs. 17.5 months (95% CI 1.7-19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

Austrian tricentric real-life analysis of molecular profiles of metastatic biliary tract cancer patients.

Introduction: Metastatic biliary tract cancer (BTC) is a rare and aggressive entity associated with poor prognosis. It represents a major challenge for adequate treatment strategies. In recent years, BTC has become a model for precision medicine in gastrointestinal oncology. Therefore, the analysis of the individual molecular profile in BTC patients may lead to targeted therapies for the benefit of patients. Methods: In this Austrian, tricentric, real-world, retrospective analysis, we investigated patients diagnosed with metastatic BTC who underwent molecular profiling between 2013 and 2022. Results: In total, 92 patients were identified in this tricentric analysis and 205 molecular aberrations, including 198 mutations affecting 89 different genes in 61 patients were found. The predominant mutations were in KRAS (n=17; 22.4%), TP53 (n=17; 22.4%), PIK3CA (n=7; 9.2%), FGFR2 (n=7; 9.2%), DNMT3A (n=7; 9.2%), IDH1 (n=7; 9.2%), IDH2 (n=6; 7.9%), CDKN2A (n=6; 7.9%), BAP1 (n=4; 5.3%), NF1 (n=4; 5.3%), and NF2 (n=4; 5.3%). Three patients had HER2 amplification. MSI-H status and FGFR2 fusion genes were each observed in two different patients. One patient had a BRAF V600E mutation. Eventually, 10 patients received targeted therapy, of whom one-half derived clinical benefit. Conclusions: Molecular profiling of BTC patients is implementable in routine clinical practice and should be regularly employed to detect and exploit molecular vulnerabilities.

Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors.

In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of our platform for precision medicine, we analyzed the molecular characteristics of 71 cancer patients. The tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite stability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after a consensus discussion. Seventy-one cancer patients with activation of the mTOR pathway were offered an mTORC1-inhibitor-based targeted therapy, and twenty-three (32.4%) of them eventually received the targeted therapy. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. The median time to treatment failure was 2.8 months. In total, 110 mutations were detected in 60 patients (84.5%). The three most frequent mutations were found in TP53, PTEN, and KRAS, which accounted for over 50% (56.4%) of all mutations. In sum, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak.

Immune Checkpoint Inhibitors for Advanced Biliary Tract Cancer.

BTC is a rare and aggressive cancer disease, bearing an overall dismal prognosis with only finite therapy options. Only combination chemotherapy regimens achieve disease control, which is often only short-lived since the tumor tissue exhibits high resistance to chemotherapy. The emergence of immune checkpoint inhibitors in recent years has significantly improved the survival of cancer patients and thus, has been integrated into the therapeutic management of several solid tumors, including melanoma, colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), triple- negative breast cancer (TNBC), and non-small-cell lung cancer (NSCLC). Investigation of the tumor biology of BTC and results of preliminary studies have shown that BTC may also be amenable to immunomodulation. In this review, we seek to give a comprehensive overview of the role, potential, and clinical significance of ICPI in the management of BTC.

Molecularly guided treatment of metastatic parotid gland carcinoma in adults.

BACKGROUND: Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. METHODS: In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. RESULTS: We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p­mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. CONCLUSION: A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

Precision Medicine for the Management of Therapy Refractory Colorectal Cancer.

In this analysis, we examined the efficacy, feasibility, and limitations of molecular-based targeted therapies in heavily pretreated metastatic colorectal cancer (mCRC) patients after failure of all standard treatments. In this single-center, real-world retrospective analysis of our platform for precision medicine, we mapped the molecular profiles of 60 mCRC patients. Tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite instability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after consensus discussion. In total, we detected 166 mutations in 53 patients. The five most frequently found mutations were TP53, KRAS, APC, PIK3CA, and PTEN. In 28 cases (47% of all patients), a molecularly targeted therapy could be recommended. Eventually, 12 patients (20%) received the recommended therapy. Six patients (10%) had a clinical benefit. The median time to treatment failure was 3.1 months. Our study demonstrates the feasibility and applicability of using targeted therapies in daily clinical practice for heavily pretreated mCRC patients. This could be used as a targeted treatment option in half of the patients.

Personalized Adjuvant Treatment of Colon Cancer.

INTRODUCTION: Colon cancer (CC) is one of the most frequent malignant diseases. Adjuvant chemotherapy is of utmost importance in the management of localized disease. With the emergence of precision medicine, treatment approaches are becoming increasingly personalized and complex. This review contributes to a broader understanding of the role and relevance of personalized adjuvant treatment strategies in colon carcinoma, and summarizes the current status in this disease entity. METHODS: We searched the websites ClinicalTrials.gov, PubMed, and ASCO (American Society of Medical Oncology) Meeting Library for clinical trials and retrospective analyses in the field of adjuvant treatment of CC with special attention to personalized approaches. RESULTS: Various factors, including gender, age, sidedness, stage, dMMR/MSI-H, mutations, molecular profile, CMS, immunoscore, minimal residual disease, type of adjuvant therapy, therapy duration, and the patient's wish play an important role in the adjuvant setting of CC and should be considered in treatment decision making. CONCLUSION: Future molecular profiling ideally assessed and monitored by liquid biopsy might personalize decision making even more in the adjuvant setting of CC patients. Further research and clinical trials are needed to clarify relevant questions and to highlight important clinical aspects.

Outcome of Targeted Therapy Recommendations for Metastatic and Recurrent Head and Neck Cancers.

Recurrent/metastatic (R/M) head and neck cancers bear a poor prognosis. In this analysis, we examined the efficacy and the outcome of targeted therapy recommendations based on the patients' molecular tumor portrait after failure of all standard therapy options. In this single-center, real-world retrospective analysis of our platform for precision medicine, we analyzed the molecular profile of 50 patients diagnosed with R/M head and neck cancer. Tumor samples of the patients were examined using next-generation sequencing panels of mutation hotspots, microsatellite instability (MSI) testing, and immunohistochemistry (IHC). In 31 cases (62.0% of all patients), a molecular-driven targeted therapy approach was recommended. Eventually, 14 patients (28%) received the suggested targeted therapy. Six of fourteen patients (43%) achieved stable disease conditions and four patients (29%) experienced a progressive disease. The median time to treatment failure was 2.8 months. Therapy recommendations were significantly more often issued for men (p = 0.037) than for women. This analysis demonstrated that precision medicine provided the basis for molecular-driven therapy recommendations in over half of the patients with advanced therapy refractory head and neck cancers, with significantly more therapy recommendations for men. Our analysis showed that although precision medicine approaches are implementable and feasible for the management of recurrent/metastatic head and neck cancers in daily clinical routine, there are major limitations and challenges that have to be overcome.

Targeted Therapy Recommendations for Therapy Refractory Solid Tumors-Data from the Real-World Precision Medicine Platform MONDTI.

Advanced therapy-refractory solid tumors bear a dismal prognosis and constitute a major challenge in offering effective treatment strategies. In this real-world retrospective analysis of our precision medicine platform MONDTI, we describe the molecular profile of 554 patients diagnosed with 17 different types of advanced solid tumors after failure of all standard treatment options. In 304 cases (54.9% of all patients), a molecular-driven targeted therapy approach could be recommended, with a recommendation rate above 50% in 12 tumor entities. The three highest rates for therapy recommendation per tumor classification were observed in urologic malignancies (90.0%), mesothelioma (78.6%), and male reproductive cancers (71.4%). Tumor type (p = 0.46), expression of p-mTOR (p = 0.011), expression of EGFR (p = 0.046), and expression of PD-L1 (p = 0.023) had a significant impact on the targeted therapy recommendation rate. Therapy recommendations were significantly more often issued for men (p = 0.015) due to gender-specific differences in the molecular profiles of patients with head and neck cancer and malignant mesothelioma. This analysis demonstrates that precision medicine was feasible and provided the basis for molecular-driven therapy recommendations in patients with advanced therapy refractory solid tumors.

Clinical characteristics and comparison of the outcome in young versus older patients with upper gastrointestinal carcinoma.

BACKGROUND: The clinical behaviour and outcome of young patients with gastroesophageal tumours (GET) is surmised to differ from older patients, yet data on the comparison of these two patient subgroups is scarce. This study focuses on the investigation of the clinical characteristics and survival outcome of younger-age people with GET, when compared to older patients. METHODS: Patients diagnosed with GET at the Medical University of Vienna between 2004 and 2016 were included in this study. Clinical parameters and the overall survival (OS) were compared between young (≤ 45 years) and elderly (≥ 65 years) patients. RESULTS: Among 796 patients, who were eligible for this analysis, fifty-eight patients (7%) were ≤ 45 years at the initial onset of the disease. These 58 young patients were then matched to elderly patients based on the gender, tumour stage, histology and tumour location. The number of metastatic lesions was significantly higher among young patients (p < 0.05). In a non-metastatic setting younger patients showed a significant longer OS than older patients (median 1226 versus 801 days, p = 0.028). Furthermore, young patients with extensive metastatic disease (2 or more metastatic site) had a significantly poorer OS than elderly patients (median 450 versus 646 days, p = 0.033). CONCLUSION: These results indicate that young patients might be diagnosed very late, which might lead to the development of a more aggressive disease compared to older patients, but a relatively long OS when diagnosed and treated in a non-metastatic setting. Thus, screening methods for younger patients might be considerable to enhance the outcome of young patients with GET.

Applied precision medicine in metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. METHODS: In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. RESULTS: In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. CONCLUSION: Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.

First evidence for the antitumor activity of nanoliposomal irinotecan with 5-fluorouracil and folinic acid in metastatic biliary tract cancer.

BACKGROUND: Therapeutic options are limited for advanced, metastatic biliary tract cancer. The pivotal NAPOLI-1 trial demonstrated the superior clinical benefit of nanoliposomal irinotecan (Nal-IRI) in gemcitabine-pretreated patients with metastatic pancreatic ductal adenocarcinoma; however, the antitumor activity of Nal-IRI in biliary tract cancer is unknown. This is the first report describing the efficacy of Nal-IRI in biliary tract cancer. METHODS: In this multicenter retrospective cohort analysis, we identified patients with metastatic biliary tract adenocarcinoma who were treated with Nal-IRI in combination with 5-fluorouracil and folinic acid following tumor progression under standard therapy at one of the study centers between May 2016 and January 2019. We assessed disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: There were 14 patients; the median age at the time of diagnosis and the median age at the initiation of Nal-IRI were 59.3 and 60.0 years, respectively. Nal-IRI in combination with 5-fluorouracil and folinic acid was administered as second-, third-, fourth-, and fifth-line treatment in 6 (43%), 5 (36%), 2 (14%), and 1 (7%) patient with metastatic disease, respectively. The objective DCR with Nal-IRI was 50% (7/14 patients). Six patients (43%) had partial response, and one patient (7%) had stable disease. Progressive disease was observed in seven patients. The median PFS and median OS following Nal-IRI initiation were 10.6 and 24.1 months, respectively. CONCLUSIONS: This retrospective analysis provides the first evidence that Nal-IRI might exhibit a clinical meaningful antitumor activity in metastatic biliary tract cancer.

Molecular Guided Treatments in Gynecologic Oncology: Analysis of a Real-World Precision Cancer Medicine Platform.

INTRODUCTION: Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, molecular guided treatments may be a viable option for the treatment of advanced gynecologic cancers. PATIENTS AND METHODS: In this single-center, real-world retrospective analysis of our platform for precision cancer medicine (PCM), we describe the molecular profiling of 72 patients diagnosed with different types of advanced gynecologic malignancies. Tumor samples of the patients were examined by next-generation sequencing panel and immunohistochemistry (IHC). RESULTS: In total, we identified 209 genetic aberrations in 72 patients. The ten most frequent alterations were TP53 (n = 42, 20%), KRAS (n = 14, 6.6%), PIK3CA (n = 11, 5.2%), PIK3R1 (n = 9, 4.3%), ATR (n = 8, 3.8%), PTEN (n = 8, 3.8%), BRCA1 (n = 6, 2.8%), NF1 (n = 4, 1.9%), NOTCH1 (n = 4, 1.9%), and POLE (n = 4, 1.9%), which account for more than half of all molecular alterations (52.6%). In 21 (29.1%) patients only one mutation could be detected, and 44 (61.1%) patients had more than one mutation. No molecular alterations were detected in seven (9.7%) patients. IHC detected expression of phosphorylated mammalian target of rapamycin and epidermal growth factor receptor in 58 (80.6%) and 53 (73.6%) patients, respectively. In over two thirds (n = 49, 68.1%), a targeted therapy was suggested, based on the identified genetic aberrations. The most frequently recommended specific treatment was the combination of everolimus with exemestane (n = 18, 25 %). CONCLUSION: Based on our observations, it seems that PCM might be a feasible approach for advanced gynecologic cancers with limited treatment options. IMPLICATIONS FOR PRACTICE: Nowadays molecular profiling of advanced gynecologic malignancies is feasible in the clinical routine. A molecular portrait should be done for every patient with an advanced therapy-refractory gynecologic malignancy to offer molecular-based treatment concepts.

PD-L1 and HER2 Expression in Gastroesophageal Cancer: a Matched Case Control Study.

Immunotherapy with check-point inhibitors serves as a promising treatment strategy in patients with upper gastrointestinal (GI) tumors. Human epidermal growth factor receptor 2 (HER2) is the only identified therapeutic target in upper GI tumors, whose potential interaction with programmed death-ligand 1 (PD-L1) is unknown. The aim of this study was the investigation of PD-L1 and HER2 in upper GI tumors. We retrospectively identified patients with HER2 positive gastroesophageal cancers and matched them with a HER2 negative group. We investigated the tumor specimens for HER2 status and PD-L1 expression, with the following assessments being performed: i) staining of tumor cells in terms of tumor proportion score (TPS), ii) staining for tumor-associated immune cells (TAIs), iii) interface pattern and iv) combined positive score (CPS). Both HER2 positive and negative group consisted of 59 patients. Expression of PD-L1 in TAIs and interface pattern were associated with a favorable outcome (p = 0.02, HR = 0.8; p = 0.04, HR = 0.39; respectively) in patients with localized disease, whereas TPS was associated with an unfavorable outcome in patients with advanced tumor (p = 0.02, HR = 1.4). These effects were HER2 independent. PD-L1 expression in its different assessment is equally observed in HER2 positive and negative patients. Future studies will show whether dual inhibition of HER2 and PD-L1 improves survival of this selected patient population.

Gender differences in molecular-guided therapy recommendations for metastatic malignant mesothelioma.

BACKGROUND: Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile. METHODS: In this single-center, real-world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next-generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off-label therapy custom-tailored to the individual patient. RESULTS: In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD-L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender-specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease. CONCLUSIONS: Our observations suggest that a molecular-guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.

Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia.

Background Monitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens. Methods We examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS. Results A good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates. Conclusions In summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.

Utilization and Efficacy of Palliative Chemotherapy for Locally Advanced or Metastatic Gastroesophageal Carcinoma.

BACKGROUND/AIM: A standard treatment recommendation for advanced stage gastroesophageal cancer is still missing. PATIENTS AND METHODS: We retrospectively analyzed clinical data of patients with inoperable locally advanced or metastatic gastroesophageal cancer treated between 2001 and 2017 at the Vienna General Hospital, Austria. RESULTS: Administration of systemic therapy was positively associated with overall survival (OS) (469 days vs. 185 days; p<0.001), while palliative gastrectomy or radiotherapy showed no correlation. OS was significantly longer in patients receiving capecitabine/oxaliplatin (XELOX) vs. leucovorin/5-FU/oxaliplatin (FOLFOX) (600 days vs. 327 days, p<0.05). Comparison of doublet vs. triplet chemotherapies showed no difference in OS, but triplet chemotherapy resulted in more adverse events. The anti-HER2-antibody trastuzumab doubled OS (836 days vs. 399 days, p=0.053). CONCLUSION: Capecitabine may be preferably used over infused 5-FU and doublet chemotherapy over triplet chemotherapy in the first-line palliative setting of advanced gastroesophageal cancer.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.