July 14, 2024

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ctDNA guides the targeted therapy of HER2-positive colorectal cancer

ctDNA guides the targeted therapy of HER2-positive colorectal cancer


Nature Medicine: ctDNA guides the targeted therapy of HER2-positive colorectal cancer.


As one of the most common malignant tumors of the digestive tract, the incidence of colorectal cancer currently accounts for the third place among all malignant tumors, and the cancer-related fatality rate has jumped to the second place , a serious threat to human health [1].

With the deepening of molecular biology research and the discovery of driving genes, the treatment of colorectal cancer has gradually developed in the direction of individualization and precision.


Human epidermal growth factor receptor 2 (HER2) has been initially confirmed as a treatment target for colorectal cancer [2].

Past studies have shown that anti-HER2 therapy has a certain curative effect and good results in patients with HER2-positive metastatic colorectal cancer (mCRC) Tolerability [3].


However, the current research shows that the overall positive rate of HER2 in colorectal cancer is not high, and there is a huge difference in the positive rate between different studies (1.6%-46.2%) [4].

This phenomenon may be different from the current scoring standards for HER2 positive in CRC organizations, and the detection of HER2 is still mainly related to immunohistochemistry or fluorescence in situ hybridization.

So, are there other more accurate methods that can assist in detecting the expression of HER2 in patients with bowel cancer?


The answer is yes.


Recently, the team of Professor Takayuki Yoshino from the National Cancer Center of Japan published the latest research results of the team in the journal Nature Medicine.


They used tumor histology testing or plasma circulating tumor DNA (ctDNA) analysis to select mCRC patients with HER2 amplification as subjects to evaluate the effect of pertuzumab combined with trastuzumab targeted therapy .


The results showed that the objective response rate (ORR) of mCRC patients with HER2-positive histology reached 30%, and the ORR of mCRC patients with ctDNA positive also reached 28%, both of which were superior to the ORR of standard salvage therapy for mCRC patients in previous real-world studies (0 %) .

Subsequent exploratory studies also found that the use of ctDNA to detect changes in the copy number of the HER2 gene before and after targeted therapy in patients can also help assess the patient’s response to treatment [5].


This result shows that the detection efficiency of ctDNA for HER2 gene is not inferior to that of tumor histology, and ctDNA can not only be used to evaluate whether HER2 gene-targeted therapy is applicable to mCRC patients , but also can be used to dynamically monitor patients’ treatment with targeted drugs. The effect helps predict the prognosis of the patient.


ctDNA guides the targeted therapy of HER2-positive colorectal cancer

Screenshot of article homepage


As a molecular detection method that has emerged in recent years, liquid biopsy technology is not only helpful for early tumor screening, but also for real-time monitoring of treatment efficacy and drug resistance genes, assessing the risk of recurrence and metastasis, and has important applications in the precise treatment of tumors. Foreground [6].

The objects of liquid biopsy include circulating tumor cells (CTC), ctDNA, exosomes, circulating RNA, etc.

Among them, ctDNA is the most important biomarker, and its application value in advanced gastrointestinal tumors has gradually been recognized [7].


Yoshino’s team has carried out a screening study (GOZILA study) in Japan, which performed second-generation plasma ctDNA sequencing on patients with advanced gastrointestinal tumors, and gave corresponding targeted drug treatments based on genotyping.

Studies have found that the application of ctDNA testing can speed up the process of patient recruitment, and its detection efficiency for patient genotyping is the same as the results of histological testing [8].

However, there are still few clinical studies using ctDNA, especially the use of ctDNA to detect gene amplification .

As a result, the Yoshino team designed this phase 2 clinical study and named it the TRIUMPH study.


The TRIUMPH study used two large-scale screening cohorts in Japan-SCRUM-Japan GI-SCREEN and GOZILA, to select some mCRC patients into the group, and the enrolled patients were subjected to histological examination [immunohistochemistry (IHC) and fluorescence in situ Hybridization (FISH)] and/or plasma ctDNA was detected as RAS wild-type gene, and the HER2 gene was amplified and expressed.


The enrolled patients were followed up after pertuzumab combined with trastuzumab targeted therapy.

The primary endpoint of follow-up was the objective response rate (ORR) . In addition, the researchers selected the RAS wild-type gene in the SCRUM-Japan Registry cohort, accompanied by HER2 gene amplification, but received mCRC patients who received a standard salvage treatment plan that does not target HER2 as the real-world control group.


From December 2017 to March 2020, of the 147 mCRC patients undergoing HER2 histological screening (HER2-Screening group), a total of 56 were confirmed to have HER2 gene amplification.

From January 2018 to March 2020, 66 of the 1107 ctDNA test (GOZILA group) patients were confirmed to have HER2 gene amplification. In addition, the researchers found that among all amplified genes measured by ctDNA, the median plasma copy number (pCN) expression of the HER2 gene was the highest, suggesting that the HER2 gene may be a driver gene and potential target gene for the progression of mCRC .


ctDNA guides the targeted therapy of HER2-positive colorectal cancer

PCN sequencing of amplified genes in GOZILA group


In the two research cohorts, a total of 75 patients underwent HER2 histology and ctDNA testing at the same time. Further analysis revealed that 7/39 (18%) patients were histologically positive and ctDNA negative (tissue+ctDNA-). And 6/38 (16%) were positive for ctDNA and negative for histology (tissue-ctDNA+).

It can be seen that the positive agreement rate between the histology and ctDNA method for the detection of HER2 gene amplification was 82%, and the overall agreement rate was 83% .


ctDNA guides the targeted therapy of HER2-positive colorectal cancer

Histology and ctDNA detection of HER2 gene amplification in patients


The Yoshino team finally selected 30 patients into the group, including 27 in the histological positive (tissue+) group, 25 in the ctDNA positive (ctDNA+) group, and 22 patients underwent both histological and ctDNA tests.

The median follow-up time of the two groups was 9.2 months in the tissue+ group and 7.6 months in the ctDNA+ group.


In addition, the researchers selected 14 patients with HER2 gene-amplified mCRC as real-world data controls. These patients have received first-line fluorouracil, oxaliplatin, irinotecan, and anti-EGFR therapy.

After the disease progresses, the most commonly used The salvage treatment is trifluridine tepipyrimidine tablets combined or not combined with bevacizumab.


ctDNA guides the targeted therapy of HER2-positive colorectal cancer

Screening process of mCRC patients enrolled in the TRIUMPH study


During the follow-up process, both groups of patients reached the main follow-up endpoint of the study. Among them, the ORR of the tissue+ group was 30%, and that of the ctDNA+ group was 28%.

One patient in both groups achieved complete remission (CR). In comparison, the ORR of the control group was 0% .


Evaluation of clinical efficacy of each group of patients


In addition, the median progression-free survival (PFS) of the tissue+ group was 4.0 months, while the median PFS of the ctDNA+ group was 3.1 months.

For the median overall survival (OS), the median OS of patients in the tissue+ group was 10.1 months, while that of patients in the ctDNA+ group was 8.8 months .


Patient’s clinical efficacy evaluation and PFS comparison


A total of 24 patients (80%) had treatment-related adverse events, the most common of which were infusion-related reactions, diarrhea, gastritis, and discomfort. Three patients (10%) had treatment-related grade 3 adverse events, but no treatment-related deaths occurred.


In order to evaluate the correlation between the patient’s baseline histology and ctDNA gene expression profile and the treatment effect, Yoshino’s team continued to carry out exploratory studies in the TRIUMPH cohort.

Histological second-generation sequencing (NGS) only detected common changes in oncogenes (such as HER2 and BRAF genes) in a small number of non-responders, while ctDNA genotyping showed that there were receptor tyrosine kinases (RTKs) in non-responding patients. )/RAS and PI3K related genes have significant amplification or clonal mutations, and these genes have been reported to be related to the resistance of HER2 targeted therapy [9].


In total, among 21 patients who did not respond to targeted therapy, histological NGS detected common mutations in RTK/RAS/PI3K-related genes in 4 patients (19%), while ctDNA was detected in 14 patients (67%). )

The mutation was detected in the patient (p=0.004) .


In addition, the researchers also found that the correlation between the HER2 copy number (CN) obtained based on histological NGS and the clinical prognosis of patients was significantly better than that of the HER2/CEP17 ratio or the HER2 CN-FISH group (p<0.001).

The correlation between absolute count and clinical prognosis is not obvious, but the correlation between CN (ApCN) and prognosis after calibration by tumor component is similar to that of histological NGS (p=0.009).


The Yoshino team further evaluated the clinical prognosis of patients based on the common mutation rate of the patients’ RTK/RAS/PI3K-related genes, and the HER2 CN detected by the histological NGS of the tissue+ group of patients or the ApCN of the ctDNA+ group.

The results showed that patients without common mutations and whose HER2 CN was higher than the threshold (ie, patients in the dominant group) had significantly increased PFS and OS .


In addition, the researchers also found that the detection of ctDNA component changes 3 weeks after targeted therapy can help assess the efficacy of patients.

The median percentage of ctDNA components before and after treatment in patients who achieve objective remission is less than 1.0, while tumors The ctDNA component of progressive patients was significantly increased, and the decrease of ctDNA after treatment was significantly related to the better PFS and OS of the patients.

Through further analysis of the plasma ctDNA before and after targeted therapy, it was found that of the 26 patients with disease progression, 16 (62%) had detected acquired mutations or amplifications in at least one gene.


Changes in biomarkers before and after treatment


In general, this prospective phase 2 clinical trial showed that for mCRC patients with HER2 amplification, the ORR of Pertuzumab combined with Trastuzumab is close to 30%, and the effectiveness of the study is less than that of The safety is consistent with previous studies, and the efficacy of ctDNA and histological tests for HER2 amplification is similar.


In addition, the dynamic changes of ctDNA before and after treatment can help evaluate the efficacy of patients, and can predict the patient’s secondary drug resistance based on the gene mutation and amplification after treatment, which is important for predicting the prognosis of patients with HER2-positive mCRC Application prospects

. Of course, this study is still a small sample size study, and more large-scale studies are needed for verification in the future.





1.Sung, H., et al., Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021. 71(3): p. 209-249.

2.Greally, M., C.M. Kelly, and A. Cercek, HER2: An emerging target in colorectal cancer. Curr Probl Cancer, 2018. 42(6): p. 560-571.

3.Sartore-Bianchi, A., et al., Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol, 2016. 17(6): p. 738-746.

4.Ingold Heppner, B., et al., HER2/neu testing in primary colorectal carcinoma. Br J Cancer, 2014. 111(10): p. 1977-84.

5.Nakamura, Y., et al., Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nat Med, 2021. 27(11): p. 1899-1903.

6.Alix-Panabières, C., The future of liquid biopsy. Nature, 2020. 579(7800): p. S9.

7.Nakamura, Y. and K. Shitara, Development of circulating tumour DNA analysis for gastrointestinal cancers. ESMO Open, 2020. 5(Suppl 1): p. e000600.

8.Nakamura, Y., et al., Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med, 2020. 26(12): p. 1859-1864.

9.Pietrantonio, F., et al., Biomarkers of Primary Resistance to Trastuzumab in HER2-Positive Metastatic Gastric Cancer Patients: the AMNESIA Case-Control Study. Clin Cancer Res, 2018. 24(5): p. 1082-1089.

ctDNA guides the targeted therapy of HER2-positive colorectal cancer

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