Liquid Biopsy Tracks Herceptin Resistance in HER2+ Gastric Cancer


Liquid biopsy of circulating tumor DNA (ctDNA) is an “efficient” way to monitor resistance to trastuzumab (Herceptin, Genentech) and spot emerging resistance mechanisms in metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer, according to a study from China.

Up to 23% of gastric cancers are HER2+, but the response rate of these tumors to trastuzumab is limited, and any resistance to the drug happens rapidly during treatment, De-Shen Wang, MD, PhD, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China, told Medscape Medical News.

“Currently, the underlying mechanism of trastuzumab resistance remains unclear, and strategies to overcome resistance are urgently needed,” said Wang.

“We found that liquid biopsy-based ctDNA profiling could promisingly predict the tumor shrinkage and progression, and the underlying mechanism for innate resistance and acquired resistance of Herceptin might be different due to the differences of observed HER2 copy numbers,” Wang added.

The study was published online in the journal Gut.

Researchers evaluated the consistency between molecular alterations in solid tumor biopsies and liquid (plasma) biopsies by sequencing a panel of 416 cancer-related genes from 78 patients with gastric cancer (46 HER2+ and 32 HER2–). They also performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track resistance during trastuzumab treatment and validate candidate resistance genes identified.

The molecular alterations detected in plasma provided a “good representation of the status of the tumor tissue, particularly at advanced stages,” the authors report in their article.

HER2 somatic copy number alterations (SCNA) were “highly consistent” with fluorescence in situ hybridization data, and the detected HER2 copy number variation was better than the plasma carcinoembryonic antigen level at predicting tumor shrinkage and progression, they note.

Most patients with innate trastuzumab resistance had high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance, they found.

PIK3CA/R1/C3 or ERBB2/4 mutations contributed “greatly” to resistance and led to worse progression free survival, whereas ERBB4 S774G mutation increased sensitivity to trastuzumab, Wang said.

The researchers also identified and confirmed NF1 as a resistance-related gene and found evidence that the combination of the HER2 inhibitor lapatinib (Tykerb, GlaxoSmithKline) and MEK/ERK inhibitor selumetinib (AstraZeneca) might overcome trastuzumab resistance.

“We propose that ctDNA profiling could provide helpful information to monitor the occurrence, dissect the potential molecular mechanisms, and provide helpful clues to therapy development for Herceptin resistance,” Wang told Medscape Medical News.

However, the technique, and this study, has several limitations, the authors note. First, although the 416-gene panel covered the majority of solid tumor-related genes, patients might have developed a mutation in a gene not covered by the panel. It’s also possible that the function of a protein encoded by a certain gene was regulated at the transcriptional, translational, or even post-translational level, and thus was not detected by DNA sequencing, they explain.

Second, they note that cell-free DNA (cfDNA) from plasma contains both cfDNA released from normal cells and ctDNA from limited tumor cells, leading to a lower tumor DNA content in the whole plasma cfDNA sample in most cases, which generates large amounts of “noise” and limits ctDNA detection sensitivity.

“A higher sequencing coverage depth might improve the detection sensitivity of ctDNA profiling to a certain extent but would not completely solve the problem due to the limited number of original tumor DNA molecules present in the cfDNA sample,” the authors suggest.

Patients with Peritoneal Carcinomatosis from Gastric Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Is Cure a Possibility?


Abstract

BACKGROUND:

Peritoneal carcinomatosis is an increasingly common finding in gastric carcinoma. Previously, patients were treated as terminal, and median survival was poor. The use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in this context is still highly debatable.

OBJECTIVE:

The aim of this study was to evaluate the long-term outcomes associated with CRS and HIPEC, and define prognostic factors for cure, if possible.

PATIENTS AND METHODS:

All patients with gastric carcinomatosis from five French institutions who underwent combined complete CRS and HIPEC and had a minimum follow-up of 5 years were included in this study. Cure was defined as a disease-free interval of more than 5 years from the last treatment until the last follow-up.

RESULTS:

Of the 81 patients who underwent CRS and HIPEC from 1989 to 2009, 59 had a completeness of cytoreduction score (CCS) of 0 (complete macroscopic resection), and the median Peritoneal Cancer Index (PCI) score was 6. Mitomycin C was the most commonly used drug during HIPEC (88 %). The 5-year overall survival (OS) rate was 18 %, with nine patients still disease-free at 5 years, for a cure rate of 11 %. All ‘cured’ patients had a PCI score below 7 and a CCS of 0. Factors associated with improved OS on multivariate analysis were synchronous resection (p = 0.02), a lower PCI score (p = 0.12), and the CCS (p = 0.09).

CONCLUSION:

The cure rate of 11 % for patients with gastric carcinomatosis who are deemed terminal emphasizes that CRS and HIPEC should be considered in highly selected patients (low disease extent and complete CRS).

Licochalcone A inhibits growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis


The aim of this study was to determine the anticancer effects of seven licorice compounds in MKN-28, AGS, and MKN-45 gastric cancer cells and human gastric epithelium immortalized cells. We also explored the mechanism of action of licochalcone A (LCA), the most cytotoxic licorice compound, by analyzing its influence on cell cycle progression and apoptosis. The results indicated that LCA was the most cytotoxic licorice compound of those tested, and it inhibited gastric cancer cells growth in a dose-dependent manner, with an IC50 value of approximately 40μM. LCA affected gastric cancer cell viability by blocking cell cycle progression at the G2/M transition and inducing apoptosis. LCA treatment increased the expression of Rb and decreased the expression of cyclin A, cyclin B and MDM2 in MKN-28, AGS and MKN-45 cell lines. In addition, LCA-induced apoptosis by its effects on the expression of PARP, caspase-3, Bcl-2 and Bax. These data provide evidence that LCA has the potential to be used in the treatment of gastric cancer.

source: cancer letter