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, 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."

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.

DNA sequencing

"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 have 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 is 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.