The precise treatment of colorectal cancer (CRC) requires additional attention to several key gene loci. In addition to the RAS gene that affects the efficacy of drugs such as cetuximab and MSI/PD-L1 that affects immune therapy related indicators, HER2 gene abnormalities are also a common treatment entry point in colorectal cancer.

The impact of HER2 amplification

Among them, HER2 amplification with mature treatment regimens accounts for approximately 2% to 3% of the total CRC patients; However, the treatment of point mutation is still unclear, and its proportion in CRC patients is about 2%. The coexistence of HER2 amplification and point mutation also exists, accounting for about 0.5% of the total number of CRC according to research.

In June 2021, researchers from the National Medical Center of the City of Hope in the United States reported a case of coexistence of HER2 amplification and point mutation, and pointed out that the patient used trastuzumab combined with lapatinib in the treatment, and achieved good therapeutic effect until drug resistance was caused by other gene mutations.

Note: Lapatinib is a small molecule tyrosine kinase inhibitor (TKI) targeting HER2 and EGFR.

Case related articles,

Published in the Journal of the National Comprehensive Cancer Network

Basic information and early treatment of patients

The patient is a 59 year old male who was diagnosed with T3N0 poorly differentiated rectal adenocarcinoma in November 2016 due to rectal bleeding. From November 2016 to January 2017, he received radiotherapy and chemotherapy based on capecitabine and achieved complete remission. Afterwards, he chose to observe and did not undergo further maintenance treatment.

In June 2017, the disease recurred with distant lymph node metastasis. The biopsy results of the distal metastasis of the clavicle lymph node showed that the metastasis was RAS/BRAF wild-type, microsatellite stable (MSS) adenocarcinoma, consistent with the situation of the main lesion. This time, the patient was treated with FOLFOX+bevacizumab combination therapy, which lasted from July 2017 to November 2017, and achieved excellent efficacy. Later, the lymph node metastases were treated with radiotherapy consolidation.

Multiple relapses, genetic testing

Detect the coexistence of HER2 amplification and point mutation

The disease progressed again in May 2018 and spread to the liver. This time, a treatment regimen of FOLFIRI+Panizumab was used for 6 cycles. Imaging showed some relief, and after that, three liver metastases were treated with radiofrequency cauterization. In November 2018, the patient developed intestinal obstruction due to recurrence of the primary lesion and must undergo ostomy treatment. During the surgery, a metastatic lesion was found in the peritoneum, which was confirmed by a subsequent biopsy.

After the patient was transferred to the hospital, they underwent liquid biopsy ctDNA testing to detect the mechanisms that may lead to resistance to EGFR therapy. The results showed that plasma HER2 amplification was positive (copy number was 8.1), and there were HER2 S310F point mutation, TP53 S127fs mutation and MYC amplification.

The use of targeted drug combinations significantly improves the condition

Based on previous studies related to HER2 amplification and HER2 S310F point mutation, patients were treated with dual targeted combination therapy of HER2 (trastuzumab+lapatinib). Since December 2018, patients will be given intravenous injection of trastuzumab at the initial dose of 8mg/kg, and then 6 mg/kg once every three weeks, supplemented by 1000 mg of lapatinib orally every day.

Within two months, the patient's ECOG score increased from 2 to 0, while the indicator of tumor marker CA19-9 antigen also significantly decreased. After 8 cycles, the imaging results showed a significant reduction in the tumor lesion. The patient received a total of 13 courses of treatment during this stage, with significant results.

In August 2019, the patient experienced disease progression. Using the same liquid biopsy ctDNA test, the results showed that HER2 amplification copies increased (8.1>14.8), HER2 S310F mutation allele frequency increased (72.3% ->85.6%), and HER2 G1189fs mutation and FGFR2 amplification were added, accompanied by KRAS G12V, PIK3CAR88Q, PIK3CA E545K, TP53 S127fs mutation and MYC amplification

Comparison between the results of sequencing again after the progress of targeted drugs and the first results,

It can be seen that there are already mutation copy numbers/ Increased frequency,

And there has been a new mutation

Biopsy of liver metastases confirmed the presence of HER2 copy number amplification and HER2 S310F mutations, with additional detection of PIK3R1 E17fs mutations, FANCD2 mutations, and MYC amplification. Follow up treatment included chemotherapy drugs, trastuzumab+Parstuzumab and antibody coupling drugs. The condition is repeated and is still under observation.

Conclusion

Using trastuzumab based anti HER2 targeting inhibitor or Parstuzumab, HER2 amplification in colorectal cancer has significant efficacy in many clinical trials. However, because different sites of HER2 point mutation have different effects on protein structure, it can only be analyzed separately for specific hot spots to evaluate its impact on treatment.

The point mutation of HER2 S310F in this case showed sensitivity to anti HER2 therapy in the preliminary study and practice, so the targeted therapy of trastuzumab combined with lapatinib in this case has achieved remarkable results. It should be noted that there are many known sites leading to drug resistance in the point mutation of HER2, such as L755S, V842I, D769Y and K753E. Therefore, specific case specific analysis is required for HER2 mutations.

Nevertheless, the combination of anti HER2 drugs provides a new treatment approach for colorectal cancer. I hope that relevant research can be deeply explored and benefit more patients as soon as possible.