ABSTRACT
Purpose@#The human epidermal growth factor receptor 2 (HER2) is an established therapeutic target for various kinds of solid tumors. HER2 amplification occurs in approximately 1% to 6% of colorectal cancer. In this study, we aimed to assess the efficacy and safety of trastuzumab in combination with chemotherapy in HER2-positive metastatic colorectal cancer (mCRC). @*Materials and Methods@#An open-label, phase II trial (Clinicaltrials.gov: NCT03185988) was designed to evaluate the antitumor activity of trastuzumab and chemotherapy in HER2-positive digestive cancers excluding gastric cancer in 2017. Patients from this trial with HER2-positive, KRAS/BRAF wild-type, unresectable mCRC were analyzed in this manuscript. Eligible patients were treated with trastuzumab (8 mg/kg loading dose and then 6 mg/kg every 3 weeks) and irinotecan (120 mg/m2 days 1 and 8 every 3 weeks). The primary endpoint was the objective response rate. @*Results@#Twenty-one HER2-positive mCRC patients were enrolled in this study. Seven patients (33.3%) achieved an objective res-ponse, and 11 patients (52.4%) had stable disease as their best response. The median progression-free survival (PFS) was 4.3 months (95% confidence interval, 2.7 to 5.9). Four of the 21 patients (19.0%) had grade 3 adverse events, including leukopenia, neutropenia, urinary tract infection, and diarrhea. No treatment-related death was reported. Exploratory analyses revealed that high tumor tissue HER2 copy number was associated with better therapeutic response and PFS. Alterations in the mitogen-activated protein kinase pathway, HER2 gene, phosphoinositide 3-kinase/AKT pathway, and cell cycle control genes were potential drivers of trastuzumab resistance in mCRC. @*Conclusion@#Trastuzumab combined with chemotherapy is a potentially effective and well-tolerated therapeutic regimen in mCRC with a high HER2 copy number.
ABSTRACT
Peritoneal metastasis is one of the most frequent metastatic patterns of advanced gastric cancer, but the mechanism underlying remains unclear. The 'seed and soil’ theory is now well recognized for peritoneal metastasis of gastric cancer at present. The combination of various cells, extracellular matrix, and ascites components within the abdominal cavity provide a suitable microenvironment for the plantation, infiltra-tion, growth and metastasis of gastric cancer cells. Fully under-standing of peritoneal microenvironment will help to diagnose the peritoneal metastasis of gastric cancer and tumor recurrence, and provide theoretical basis for the development of drugs targeting peritoneal microenvironment. The authors review the main cell formation, ascites and immune microenvironment involved in the formation of the peritoneal microenvironment based on relevant literatures at home and abroad, and investigate the relationship between peritoneal microenvironment and peritoneal metastasis of gastric cancer.
ABSTRACT
Objective:To investigate the infrequent gene mutations of KRAS, NRAS and BRAF in colorectal cancer and their clinical significance.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 1 513 patients with colorectal cancer who were admitted to the Peking University Cancer Hospital from December 2013 to November 2018 were collected. There were 921 males and 592 females, aged from 15 to 97 years, with an average age of 59 years. The genomic DNA of tumor tissue was extracted, and the mutation status of KRAS (exon 2, 3), NRAS (exon 2, 3) and BRAF (exon 15) was detected by the Sanger sequencing. Observation indicators: (1) mutation status of KRAS, NRAS and BRAF; (2) relationship of different mutation status of KRAS, NRAS and BRAF with clinicopathological characteristics; (3) infrequent mutation status of single gene and its clinicopathological characteristics; (4) simultaneous mutations of two genes and their clinicopathological characteristics. Count data were expressed by absolute numbers or percentages, and comparison between groups was analyzed by the chi-square test.Results:(1) Mutation status of KRAS, NRAS and BRAF: the mutation rates of KRAS, NRAS and BRAF were 37.806%(572/1 513), 3.173%(48/1 513) and 5.486%(83/1 513) of the 1 513 patients with colorectal cancer, respectively. The mutation rates of exon 2 and exon 3 in KRAS were 35.889%(543/1 513) and 1.917%(29/1 513), respectively. The mutation rates of exon 2 and exon 3 in NRAS were 1.322%(20/1 513) and 1.851%(28/1 513), respectively. The mutation rate of exon 15 in BRAF was 5.486%(83/1 513). The mutation of KRAS mainly occurred in codon 12, 13 of exon 2 and codon 61 of exon 3, with a mutation rate of 27.759%(420/1 513), 7.733%(117/1 513), and 1.586%(24/1 513), respectively. Infrequent mutation in codon 14, 59, 60 of KRAS were found in 7 patients with colorectal cancer [0.463%(7/1 513)], including V14I mutation in 2 cases [0.132%(2/1 513)], A59T mutation in 2 cases [0.132%(2/1 513)], A59E mutation in 2 cases [0.132%(2/1 513)] and G60D mutation in 1 case [0.066%(1/1 513)]. The mutation of NRAS mainly occurred in codon 12, 13 of exon 2 and codon 61 of exon 3, including Q61K with a mutation rate of 0.925%(14/1 513), followed by G12D with a mutation rate of 0.727%(11/1 513). The mutation rates of Q61R, Q61H, Q61L, G13R, G12C, G12V, G12S, G13D, and G13C were relatively low. The mutation of BRAF mainly occurred in codon 600 of exon 15 as V600E mutation, with a mutation rate of 4.957%(75/1 513). Infrequent mutation in BRAF were found in 8 patients with colorectal cancer, with a mutation rate of 0.529%(8/1 513), including D594G mutation in 5 cases [0.330%(5/1 513)], D594H mutation in 1 case [0.066%(1/1 513)], S607T mutation in 1 case [0.066%(1/1 513)], and 599-600 codon insertion AGA in 1 case [0.066%(1/1 513)]. Of the 1 513 patients, 4 [0.264%(4/1 513)] had simultaneous mutations at codon 12 and 13 of KRAS, including 2 [0.132%(2/1 513)] with simultaneous mutations at G12V and G13D, 1 [0.066%(1/1 513)] with simultaneous mutations at G12D and G13A, and 1 [0.066%(1/1 513)] with simultaneous mutations at G12V and G13F. In addition, 1 patient [0.066%(1/1 513)] had simultaneous mutations at G13D of KRAS and G12S of NRAS, and 1 patient [0.066%(1/1 513)] had simultaneous mutations at G12C of KRAS and Q61H of NRAS. (2) Relationship of different mutation status of KRAS, NRAS and BRAF with clinicopathological characteristics: patients with different tumor location and tumor differentiation degree had significantly different KRAS mutation status ( χ2=25.317, 4.166, P<0.05); patients with different gender, tumor location, tumor differentiation degree, and lymph node metastasis had significantly different BRAF mutation status ( χ2= 11.290, 22.317, 38.035, 12.611, P<0.05). The proportion of Q61K mutation and Q61R mutation of NRAS in the patients with age of < 65 and ≥ 65 years was 12/18, 2/10 and 1/18, 5/10, respectively, showing significant differences between the two groups ( χ2=5.600, 7.542, P<0.05). (3) Infrequent mutation status of single gene and its clinicopathological characteristics: 15 of the 1 513 patients had single gene mutation. Of the 7 patients with infrequent mutations in codon 14, 59 and 60 of KRAS, 6 were males and 1 was female; 6 were < 65 years old and 1 was ≥ 65 years old; 3 had tumors located in the left colon, 3 in the right colon and 1 in the rectum; 6 had highly or moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 6 were in stage Ⅳ and 1 was in stage Ⅱ of TNM staging; 6 had distant metastasis and 1 had no distant metastasis; 3 had lymph node metastasis and 4 had no lymph node metastasis; there was no postoperative recurrence. Of the 8 patients with infrequent gene mutation of BRAF, 4 were males and 4 were females; 4 were < 65 years old and 4 were ≥ 65 years old; 5 had tumors located in the left colon, 1 in the right colon and 2 in the rectum; 7 had moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 5 were in stage Ⅳ, 2 in stage Ⅲ, and 1 in stage Ⅱ of TNM staging; 6 had distant metastasis and 2 had no distant metastasis; 3 had lymph node metastasis and 5 had no lymph node metastasis; 1 had postoperative recurrence. (4) Simultaneous mutations of two genes and their clinicopathological characteristics: 6 of the 1 513 patients had simultaneous mutations of two genes. Of 6 patients with simultaneous mutations of two genes, 5 were males and 1 was female; 2 were < 65 years old and 4 were ≥ 65 years old; 1 had tumor located in the left colon, 4 in the right colon and 1 in the rectum; 5 had highly or moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 5 were in stage Ⅳ and 1 was in stage Ⅱ of TNM staging; 4 had distant metastasis and 2 had no distant metastasis; 3 had lymph node metastasis and 3 had no lymph node metastasis; 1 had postoperative recurrence. Conclusions:The infrequent mutations of KRAS and BRAF in colorectal cancer often occur in the rare codon region and mainly are point mutations. Different mutations of KRAS, NRAS and BRAF are related to clinicopathological features, which provide an important basis for treatment of colorectal cancer.