Two-point-NGS analysis of cancer genes in cell-free DNA of metastatic cancer patients.

BACKGROUND: Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti-HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. METHODS: We assessed the status of a large panel of cancer driver genes by cell-free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. RESULTS: The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two-points-Next-Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). CONCLUSIONS: Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two-point-NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.

Gemcitabine plus nab-paclitaxel followed by maintenance treatment with gemcitabine alone as first-line treatment for older adults with locally advanced or metastatic pancreatic cancer.

OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of the combination Gemcitabine (Gem) plus nab-Paclitaxel (NabP) (Gem/NabP), followed by maintenance Gem in older adults with locally advanced or metastatic pancreatic cancer (PC). MATERIALS AND METHODS: In this prospective observational study, the induction chemotherapy consisted of NabP 125 mg/m2 followed by Gem 1000 mg/m2 on days 1, 8, and 15 of a 4-week cycle. After a maximum of 3 cycles, patients without evidence of progressive disease (PD) were administered Gem 1000 mg/m2 weekly for 3 of 4 weeks as maintenance therapy until documentation of PD or unacceptable toxicity. The primary endpoint was six-month disease-control rate (DCR). RESULTS: Overall, 36 patients >70 years with metastatic or locally advanced PC were enrolled at participating Institutions. After completion of Gem/NabP, 18 (50%) patients achieved partial response, 13 (36%) had stable disease, and 5 (14%) had PD. Thirty-one patients (86%) received Gem monotherapy as maintenance treatment for a median of 3 cycles (range, 2-9 cycles). Six-month DCR was 61% (95% CI, 45-77), median PFS was 6.4 months (95% CI, 5.4-8.3), and median OS was 13.4 months (95% CI, 11.1-16.7). During Gem/NabP regimen, the most common grade 3 toxicity included neutropenia (22%), anemia (19%) and thrombocytopenia (8%). Grade 3 neuropathy was not observed. During Gem maintenance therapy, grade 3 hematological toxicity was described in 6 patients (19%). CONCLUSION: Gem/NabP followed by maintenance Gem appears to be safe and effective for older patients with locally advanced or metastatic PC.

Pathological response and outcome after neoadjuvant chemotherapy with DOC (docetaxel, oxaliplatin, capecitabine) or EOF (epirubicin, oxaliplatin, 5-fluorouracil) for clinical T3-T4 non-metastatic gastric cancer.

PURPOSE: In this prospective observational study, we sought to compare the efficacy and safety of docetaxel + oxaliplatin + capecitabine (DOC) with epirubicin + oxaliplatin + 5-fluouracil (EOF) as neoadjuvant chemotherapy (NAC) for clinical T3 or T4 non-metastatic gastric cancer (GC) patients. METHODS: The DOC NAC consisted of docetaxel 35 mg/m2 (days 1-8), oxaliplatin 85 mg/m2 (day 1), and capecitabine 750 mg/m2 twice daily (days 1-14), every 3 weeks. The EOF NAC consisted of intravenous (IV) epirubicin 50 mg/m2 combined with IV oxaliplatin 130 mg/m2 on day 1 and continuous infusion 5-fluouracil 750 mg/m2 on days 1-5, every 3 weeks. After 4 cycles of NAC or upon progression during chemotherapy, patients underwent gastrectomy with standard D2 or D3 lymphadenectomy. Pathological complete response rate per Becker tumor regression grading system was the primary endpoint and the secondary endpoints included progression-free survival (2-yr PFS) and 2-year overall survival (2-yr OS) and tolerability. RESULTS: Overall, we identified 63 patients with T3-4 non-metastatic GC starting either NAC regimen between January 2010 and December 2017 at our Institution: 34 in the DOC group and 29 in EOF group. Thirty patients (88%) in the DOC group and 22 (76%) in the EOF group completed the 4 planned cycles of NAC. Fifty-seven patients received surgery. Results indicated no statistical significant differences between the two groups, and only a trend for some better data in favour of the DOC group. The R0 resection rate was 90.6% and 88.0% for the DOC and EOF cohorts, respectively. The pathological complete response rate was 6.2% in the DOC group and 4.0% in the EOF group. Becker 1-2 pathological response was found in 46.8% of the DOC cohort and 28.0% of the EOF cohort (p = .14). The 2-yr PFS rate was 54.1% for DOC vs. 41.4% for EOF (p = .14) and the 2-yr OS rate was 80.8% for DOC vs. 58.6% for EOF (p = .05). Neutropenia was the most common grade ≥3 toxicity and occurred in 8 (23.5%) patients of the DOC group and 10 (34.4%) patients of the EOF group (p = .33). CONCLUSIONS: These findings seem to confirm the feasibility of NAC for clinically T3 and T4 non-metastatic GC and, despite no statistical significant difference was documented, suggest a trend for better activity and tolerability for the docetaxel-based regimen (DOC) compared to the epirubicin-based combination (EOF).

Capecitabine Plus Oxaliplatin and Bevacizumab, Followed by Maintenance Treatment With Capecitabine and Bevacizumab for Patients Aged > 75 Years With Metastatic Colorectal Cancer.

BACKGROUND: The aim of the present study was to evaluate the efficacy and safety of the combination of CAPOX-Bev (capecitabine [Cap] plus oxaliplatin and bevacizumab [Bev]), followed by maintenance Cap and Bev, for patients with metastatic colorectal cancer (mCRC) and aged > 75 years. PATIENTS AND METHODS: The regimen consisted of intravenous oxaliplatin 130 to 100 mg/m2 on day 1, oral Cap 750 to 1000 mg/m2 twice daily on days 1 to 14, and Bev 7.5 mg/kg on day 1, every 3 weeks. After 4 cycles of CAPOX-Bev, the patients without evidence of disease progression received maintenance treatment with Cap 1000 to 1250 mg/m2 twice daily on days 1 to 14 and Bev 7.5 mg/kg on day 1, every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was the 9-month disease control rate. Progression-free survival (PFS), overall survival (OS), and safety were the secondary endpoints. RESULTS: Overall, 36 patients were enrolled from March 2012 to April 2017 at our institution. After completion of CAPOX/Bev, 15 patients (41.7%) had a partial response, 18 (50.0%) had stable disease, and 3 (8.3%) had progressive disease. Thirty-three patients (91.7%) received the Cap/Bev regimen as maintenance treatment for a median of 8.6 cycles (range, 3-14 cycles). The 9-month DCR was 58.3% (95% confidence interval [CI], 40.8-74.5), the median PFS was 8.8 months (95% CI, 6.7-10.3 months), and the median OS was 20.8 months (95% CI, 16.1-25.4 months). With the CAPOX/Bev regimen, the most common grade 3 toxicity included neutropenia (11.1%), diarrhea (5.5%), nausea/vomiting (2.8%), and fatigue (2.8%). Grade 3 neurotoxicity was not observed. With Cap/Bev maintenance therapy, grade 3 hand-foot syndrome was observed in 2 patients (6.0%). CONCLUSION: CAPOX/Bev, followed by Cap/Bev as maintenance treatment, is safe and effective in terms of PFS and OS for elderly patients aged > 75 years with mCRC.