Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice.

PURPOSE: The pan-cancer presence of microsatellite instability (MSI)-positive tumors demonstrates its clinical utility as an agnostic biomarker for identifying immunotherapy-eligible patients. Additionally, MSI is a hallmark of Lynch syndrome (LS), the most prevalent cancer susceptibility syndrome among patients with colorectal and endometrial cancer. Therefore, MSI-high results should inform germline genetic testing for cancer-predisposing genes. However, in clinical practice, such analysis is frequently disregarded. METHODS: A next-generation sequencing (NGS)-based technique was used for MSI analysis in 4,553 patients with various tumor types. Upon request, somatic BRAF gene analysis was conducted. In addition, hereditary testing of cancer-associated genes was performed in MSI-high cases using a capture-based NGS protocol. MLH1 promoter methylation analysis was conducted retrospectively in patients with colorectal and endometrial cancer to further investigate the origin of MSI at the tumor level. RESULTS: The MSI positivity rate for the entire cohort was 5.27%. Endometrial, gastric, colorectal, urinary tract, and prostate cancers showed the highest proportion of MSI-high cases (15.69%, 8.54%, 7.40%, 4.55%, and 3.19%, respectively). A minority of 45 patients (22.73%) among the MSI-high cases underwent germline testing to determine whether the mismatch repair pathway deficiency was inherited. 24.44% of those who performed the genetic test carried a pathogenic variant in an LS-associated gene. Three MSI-high individuals had non-LS gene alterations, including BRCA1, BRCA2, and CDKN2A pathogenic variants, indicating the presence of non-LS-associated gene alterations among MSI-high patients. CONCLUSION: Although MSI analysis is routinely performed in clinical practice, as many as 77% of MSI-high patients do not undergo LS genetic testing, despite international guidelines strongly recommending it. BRAF and MLH1 methylation analysis could shed light on the somatic origin of MSI in 42.50% of the MSI-high patients; however, MLH1 analysis is barely ever requested in clinical practice.

Only 32.3% of Breast Cancer Families with Pathogenic Variants in Cancer Genes Utilized Cascade Genetic Testing.

BACKGROUND: Hereditary cancer predisposition syndromes are responsible for approximately 5-10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. METHODS: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. RESULTS: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. CONCLUSIONS: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Safety and Efficacy of RAD001 (Everolimus) Administered Upon Relapse During or After Adjuvant Treatment in Post-menopausal Women With Hormone Receptor Positive, HER2/neu Negative Locally Advanced or Metastatic Breast Cancer (CRAD001JGR08 "MELPOMENI" study).

BACKGROUND/AIM: This study aimed to provide real-world safety and effectiveness data of everolimus (EVE) plus exemestane (EXE) in estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: This prospective observational study was conducted by 19 hospital-based oncologists in Greece. Eligible patients were treated with EVE+EXE in the first-line setting; EVE was initiated according to the approved label. RESULTS: Overall, 75 eligible patients (mean age: 66.9 years; visceral metastases: 49.3%; bone-only metastases: 37.3%) were included in the effectiveness analyses. Over a median (interquartile range) of 12.1 months (range=4.2-20.5 months) of EVE treatment, the median progression-free survival was 18.0 months and the overall response rate was 22.7%. Among patients that received ≥1 EVE dose (n=80), the incidence of EVE-related adverse events was 72.5% (serious: 55.0%); stomatitis (22.5%), fatigue (22.5%), pneumonitis (18.8%); and cough (18.8%) were the most common. CONCLUSION: In the routine care in Greece, EVE demonstrates clinical benefit and a predictable safety profile.

Mapping the location of peritoneal metastases using the peritoneal cancer index and the correlation with overall survival: a retrospective study.

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment for patients with peritoneal carcinomatosis (PC). Our objective was to identify new prognostic factors within the Peritoneal Cancer Index (PCI) score in PC patients. METHODS: 140 patients (60 ovarian, 45 colon, 14 gastric, 10 pseudomyxoma peritonei, 5 mesothelioma, 6 sarcoma) with PC treated with CRS+HIPEC from 2007 to December 2013 were retrospectively included. Tumor extent and location were assessed by the PCI and residual disease was recorded using the Completeness of Cytoreduction (CC) score. All clinical data were computed in univariate and multivariate analysis using survival as primary endpoint. RESULTS: The PCI remains the most important factor concerning the long-term survival. Involved areas 4, 5 and 8 are more favorable in survival vs areas 9, 10 and 11, which predict a significantly worse outcome (p<0.002). Prognosis varies not only depending on how many peritoneal areas are involved but also on the location of the primary tumor. CONCLUSION: We demonstrated that the involvement of different areas in the PCI system has a significant impact on the final prognosis and survival.

Short bowel syndrome after cytoreductive surgery and HIPEC: nutritional considerations.

PURPOSE: The aim of this study was to present a group of patients with <150 cm of small intestine after cytoreductive surgery (CRS)+hyperthermic intraperitoneal chemotherapy (HIPEC) and the special problems arising from this condition. METHODS: From November 2005 to November 2013, 130 patients were treated for peritoneal carcinomatosis (PC) with CRS+HIPEC. Ten patients (7.7%) were left with a short bowel due to anatomical and surgical reasons. All these patients were subjected to ileostomy. Four patients (40%) were treated for ovarian carcinoma, 4 (40%) for colon and appendiceal carcinoma, 1 for peritoneal mesothelioma and 1 patient for primary peritoneal carcinoma. The completeness of cytoreduction (CC) score was CC-0 in 4 patients (40%), CC-1 in 3 (30%) and CC-2 in 3 (30%). RESULTS: The mean length of the remaining small bowel was 105 cm (range 80-150). Mean hospitalization was 42 days vs 24 days in other patients with CRS+HIPEC (p<0.002). The daily ileostomy output increased between the 3rd to 4th week as a result of oral feeding and decreased at the 4th week due to somatostatin analogue administration and possible intestinal adaptation. The mean ileostomy output at 6 months was 810±100 ml vs 1590±210 ml the first month after CRS+HIPEC (p<0.001). The overall morbidity and mortality rate was the same as in patients without extensive resection. The impact of small bowel syndrome (SBS) on overall survival was very important, as the mean overall survival in the SBS group was 28.6 months vs 41 months in other CRS+HIPEC patients (p<0.001). CONCLUSIONS: SBS is sometimes inevitable in order to perform optimal cytoreduction. Special management is required for these patients, including special nutritional efforts and home total parenteral nutrition (TPN). Extensive small bowel resection may constitute a contraindication in the management of peritoneal carcinomatosis.

A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group.

INTRODUCTION: Frequent administration of low doses of cytotoxic drugs (metronomic chemotherapy) has been suggested to suppress tumour growth possibly by inhibiting angiogenesis. We evaluated a metronomic regimen of oral vinorelbine in pre-treated patients with advanced non-small cell lung cancer (NSCLC). METHODS: Forty-six pre-treated NSCLC patients received oral vinorelbine at a fixed dose of 50 mg three times a week. RESULTS: Treatment was administered as second-line in 12 (26·1%) patients and as third- or further-line in 34 (73·9%). Grade 3-4 neutropenia was observed in 23·9% and febrile neutropenia in 10·9%. Grade 3 fatigue was the most common severe non-hematologic toxicity (10·9%). Response rate was 10·9%; 19·6% achieved disease stabilization. Median tumour progression (TTP) was 2·2 months, median overall survival 9·4 months and the 1-year survival rate was 30·1%. CONCLUSION: The administration of metronomic oral vinorelbine is feasible and results in acceptable clinical efficacy associated with manageable toxicity in a population consisting mostly of heavily pre-treated NSCLC patients.

A phase II trial of erlotinib as front-line treatment in clinically selected patients with non-small-cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of erlotinib as front-line treatment in clinically selected patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-nine previously untreated white patients who had stage IIIB/IV pulmonary adenocarcinoma or bronchoalveolar carcinoma and who were nonsmokers or former light smokers were treated with erlotinib 150 mg daily, irrespective of the EGFR mutation status. RESULTS: In an intention-to-treat analysis, the overall response rate (ORR) was 24.5%. The median progression-free survival (PFS) was 6.7 months, the median overall survival (OS) was 15.5 months, and the 1-year survival rate was 61.3%. Among the 36 patients for whom tumor material was available, 9 (25%) had activating EGFR mutations. The ORR was 66.7% in patients with activating EGFR mutations and 14.8% in patients with wild-type EGFR (2P = .006). In patients with activating EGFR mutations, the OS has not been reached, whereas it was 12.9 months in patients with EGFR wild type (2P = .045). Twenty-four patients had a PFS of > 6 months; 11 (45.8%) of them had EGFR wild type and 7 (29.1%) had EGFR mutation. CONCLUSIONS: The selection of patients for treatment with EGFR-directed tyrosine kinase inhibitors (TKIs) should be based on mutation testing. However use of clinical (smoking status) and pathologic (adenocarcinoma) criteria may identify a subgroup of patients with advanced/metastatic NSCLC who can benefit from front-line treatment with erlotinib when mutation testing is not feasible.

Second-line paclitaxel/carboplatin versus vinorelbine/carboplatin in patients who have advanced non-small-cell lung cancer pretreated with non-platinum-based chemotherapy: a multicenter randomized phase II study.

PURPOSE: This study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non-small-cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Patients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m(2) and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m(2) orally and carboplatin AUC3; both drugs were administered on days 1 and 15. RESULTS: The overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: Platinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting.

Salvage treatment in metastatic breast cancer with weekly paclitaxel and bevacizumab.

BACKGROUND: Weekly paclitaxel (P) in combination with bevacizumab (B) is an effective regimen as initial treatment of metastatic breast cancer (MBC). We investigated in a phase II study the activity of the same regimen as salvage therapy in MBC. METHODS: Pretreated women with MBC received weekly P (90 mg/m(2) days 1, 8, 15) and B (10 mg/kg days 1, 15) every 28 days. B could continue after discontinuing P until disease progression. This was second-line chemotherapy for 30% and third-line or more for 70% of patients. RESULTS: A total of 40 patients were enrolled. Median age: 61 (range 32-80) years; postmenopausal: 80%; baseline ECOG performance status <2 in 80% of patients. Two patients (5%) achieved complete response, 10 (25%) partial response (overall response rate 30%; 95% CI 15.8-44.2), and 10 (25%) stable disease. The response rate was 28% for the patients who had previously received taxanes. After a median follow-up of 20.6 months, the median time to progression was 4.8 months (95% CI 1.7-7.8), median survival 13.0 months (95% CI 10.3-15.7), and the probability of 1-year survival 55.5%. Main grade 3-4 toxicities were neutropenia 42.5%, febrile neutropenia 5%, and asthenia 10%. There was one toxic death due to sepsis. CONCLUSION: The PB regimen is well tolerated and active as salvage therapy in pretreated women with MBC. It could be an effective option even for patients exposed to taxanes during prior treatments.

Α multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer.

PURPOSE: To evaluate efficacy and toxicity of a combination of pegylated liposomal doxorubicin and irinotecan in patients with refractory small-cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with early relapse after first-line therapy with cisplatin/etoposide were treated with pegylated liposomal doxorubicin 15 mg/m(2) and irinotecan 125 mg/m(2) on days 1 and 15. Treatment was repeated every 28 days. RESULTS: A total of 144 chemotherapy courses were administered. All patients were evaluable for toxicity and twenty-six (84%) for response. Grade 3 neutropenia occurred in two (6.5%) patients and grade 1 thrombocytopenia in one (3.2%). Fatigue was the most frequent grade 3 non-hematologic toxicity and was observed in seven patients (23%). Four (12.9; 95% CI: 1.1-24.7%) patients achieved a partial response, and disease stabilization was observed in additional two (6.5%) patients (Tumor Growth Control: 19.4; 95% CI: 5.5-33.3%). The median TTP was 2.03 months, and the median survival time was 3.16 months. CONCLUSIONS: The combination of pegylated doxorubicin and irinotecan is very well tolerated but with modest activity in patients with refractory SCLC.

Second-line chemotherapy with capecitabine (Xeloda) and docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial.

PURPOSE: To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas. PATIENTS AND METHODS: Patients with pancreatic adenocarcinoma, pre-treated with gemcitabine-based chemotherapy, were treated with capecitabine (800 mg/m(2) orally, twice a day for 14 days) and docetaxel (75 mg/m(2) i.v, on day 1), every 3 weeks. The primary end-point was overall response rate (RR). RESULTS: Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0-1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80-48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4 months (95% CI: 1.6-3.13) and the median overall survival (OS) was 6.3 months (95% CI: 3.38-9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%. CONCLUSION: The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer.

Oxaliplatin as first-line treatment in inoperable biliary tract carcinoma: a multicenter phase II study.

BACKGROUND: A multicenter phase II study was conducted in order to evaluate the efficacy and safety of oxaliplatin as first-line treatment of patients with locally advanced or metastatic carcinoma of the biliary tract. PATIENTS AND METHODS: Twenty-nine chemo-naïve patients with locally advanced or metastatic biliary tract carcinoma received oxaliplatin 130 mg/m(2) i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. RESULTS: An objective response (3 complete responses, 3 partial responses) was achieved in 6 patients (20.6%, 95% CI 5.95-35.4). Disease control (complete response, partial response and stable disease) was observed in 14 patients (48.2%). The median time to tumor progression was 3 months (range 0.7-39) and the median overall survival was 7 months (range 1-39). The 1-year survival rate was 32%. Toxicity was mild. CONCLUSION: Oxaliplatin is an active agent against biliary tract carcinoma and therefore should be further investigated in combination with other cytotoxic drugs.