Precision treatment for human epidermal growth factor receptor 2-amplified advanced rectal cancer: A case report

Abstract

BACKGROUND

Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer, some patients develop resistance to these treatments. Human epidermal growth factor receptor 2 (HER2) is overexpressed in a subset of patients with colorectal cancer and has been established as a therapeutic target.

CASE SUMMARY

This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors (ICIs) in combination with pyrotinib. The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.

CONCLUSION

ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer. Chemotherapy following disease progression could enhance efficacy synergistically.

Key Words: Rectal cancer; Human epidermal growth factor receptor 2; Programmed death 1; Pyrotinib; Chemotherapy; Case report

Core Tip: Human epidermal growth factor receptor 2-amplified advanced rectal cancer was unresponsive to conventional chemotherapy and targeted therapy in a Chinese patient. This study demonstrated the synergistic effect of combining an immune checkpoint inhibitor with pyrotinib, providing a new treatment strategy for patients with advanced rectal cancer. Following treatment with an immune checkpoint inhibitor in combination with pyrotinib, the patient achieved significant therapeutic effects as evidenced by a marked reduction in tumour size.

INTRODUCTION

The incidence and mortality rates of colorectal cancer rank third and second, respectively, among all malignant tumours, and its incidence is increasing annually[1]. Due to the non-specificity of early symptoms, 30%-40% of patients with colorectal cancer present with distant metastases at the time of diagnosis[2]. Although the advent of targeted combination therapies has significantly prolonged patient survival, the options for therapeutic drugs and their efficacy after drug-resistant progression remain limited[3]. In our department, targeted drugs are selected for patients with advanced metastatic rectal cancer who have progressed after conventional treatment based on the results of precision genetic testing in conjunction with immune checkpoint inhibitor therapy. This approach yielded good efficacy and was well-tolerated. When the disease progressed, we opted to combine single-agent chemotherapy, which remained effective.

CASE PRESENTATION

Chief complaints

The patient’s main complaints were altered bowel habits for more than two months and haematochezia for one week.

History of present illness

Two months earlier, the 59-year-old male experienced a change in bowel habits that was not given adequate attention. One week prior to presentation, this was accompanied by haematochezia; however, there were no symptoms of nausea, vomiting, or fatigue.

History of past illness

The patient denied any history of chronic conditions such as hypertension, diabetes, or other malignancies.

Personal and family history

The patient reported occasional smoking and minimal alcohol consumption. The patient’s medical history was unremarkable.

Physical examination

Upon admission, the patient’s vital signs were as follows: Body temperature 36.9°C, blood pressure 120/70 mmHg, respiratory rate 18 breaths per minute, and heart rate 80 beats per minute. An abdominal examination revealed no tenderness or rebound pain. The systemic superficial lymph nodes were not enlarged. A digital rectal examination was not performed.

Laboratory examinations

The carcinoembryonic antigen (CEA) level was 75.38 ng/mL, which was slightly elevated above the normal limits, and other routine blood tests were within normal limits.

Imaging examinations

Colonoscopy performed in March 2021 revealed a large, irregular mass with an uneven surface, friable texture, and a tendency to bleed upon contact. The mass was located 15 cm from the anal verge and occupied the entire intestinal lumen. Therefore, rectal cancer was suspected. Colonoscopic biopsy revealed rectal adenocarcinoma. Magnetic resonance imaging demonstrated a rectal tumour with surrounding infiltration and enlarged lymph nodes suggestive of rectal cancer. Computed tomography (CT) of the chest, abdomen, and pelvis revealed rectal cancer with surrounding fatty interstitial infiltration, lymph node metastasis, and multiple metastases to both the lungs and liver.

FINAL DIAGNOSIS

The clinical diagnosis was stage IV rectal cancer with metastases to the liver, lungs, and lymph nodes.

TREATMENT

Figure 1 illustrates the treatment process. Palliative chemotherapy with the 5-fluorouracil (5-FU), leucovorin, oxaliplatin (OXA) regimen was initiated on March 4, 2021, for a total of three cycles. Specifically, the treatment consisted of OXA 150 mg administered intravenously on day 1, 5-FU 0.6 g given as an intravenous bolus on day 1, and 5-FU (4 g) delivered via continuous intravenous infusion over 46 hours, repeated every two weeks (q2w). Following chemotherapy, the patient experienced severe gastrointestinal reactions, including nausea and vomiting, and grade IV bone marrow suppression, which were intolerable. Repeat CT imaging suggested disease progression.

Figure 1 Management and treatment protocol for a patient with advanced rectal cancer. FOLFOX: Oxaliplatin plus 5-fluorouracil; FOLFIRI: Irinotecan plus 5-fluorouracil; PD: Progressive disease; PR: Partial response; OXA: Oxaliplatin.

OUTCOME AND FOLLOW-UP

In April 2021, next-generation sequencing of the colorectal cancer tissue using a panel of 639 genes (method: Gene capture with high-throughput sequencing) revealed the following results: Low tumour mutation burden (2.2 mutations/mb), microsatellite low instability (36.36%), no mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma rat sarcoma viral oncogene homolog, or v-raf murine sarcoma viral oncogene homologue B (BRAF), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 amplification (copy number 33), adenomatous polyposis coli mutation (variant allele frequency 15.9%), tumor protein P53 mutation (variant allele frequency 16.80%), and cyclin-dependent kinase 12 amplification (copy number 7.5) (Table 1).

Table 1 Next-generation sequencing panel 639 assay of a patient with advanced rectal cancer.

Gene	Outcome	Abundance of mutations/copy number
KRAS	Negative	-
NRAS	Negative	-
BRAF	Negative	-
ERBB2	Amplification	33
APC	Exon16, c4348C>T, p.R1450	15.9%
CDK12	Amplification	7.5
TP53	Exon4, c.325T>A, p.F109I	16.8%
TMB	TMB-L	2.2 mutations/mb
MSI	MSI-L	36.36%

KRAS: Kirsten rat sarcoma viral oncogene homolog; NRAS: Neuroblastoma rat sarcoma viral oncogene homolog; BRAF: v-raf murine sarcoma viral oncogene homolog B; ERBB2: v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; APC: Adenomatous polyposis coli; CDK12: Cyclin-dependent kinase 12; TP53: Tumour protein P53; TMB: Tumour mutational burden; MSI: Microsatellite instability.

Palliative treatment with cetuximab in combination with the irinotecan plus 5-fluorouracil (FOLFIRI) regimen was initiated on April 26, 2021, for a total of six cycles. Specifically, the treatment consisted of cetuximab 800 mg administered intravenously on day 1, irinotecan (CPT-11) 300 mg administered intravenously on day 1, 5-FU 0.6 g administered as an intravenous bolus on day 1, and 5-FU 4 g delivered via continuous intravenous infusion over 46 hours repeated q2w. A repeat CT scan on July 12, 2021, indicated progression of the liver and lung lesions. Consequently, the treatment was changed to bevacizumab in combination with the FOLFIRI regimen on August 4, 2021, for four cycles. Specifically, the treatment consisted of bevacizumab 400 mg on day 1, CPT-11 300 mg on day 1, 5-FU 0.6 g administered as an intravenous bolus on day 1, and 5-FU 4 g delivered via continuous intravenous infusion over 46 hours, repeated q2w. On September 17, 2021, follow-up evaluation revealed stable disease. On September 23, 2021, hepatic microwave ablation was performed under ultrasonographic guidance. On October 9, 2021, an intrahepatic injection of anhydrous alcohol was administered under ultrasound guidance. Postoperative ultrasound imaging revealed that the liver lesion had decreased in size compared to that before treatment. Bevacizumab in combination with the FOLFIRI regimen was continued for an additional four cycles, starting on October 26, 2021. A follow-up CT examination conducted in December 2021 revealed that the disease had progressed further compared to previous assessments, with a notable exacerbation of perianal swelling.

Following the failure of multiple conventional treatments, a comprehensive literature review indicated that the combination of immunotherapy and small-molecule targeted drugs exhibits a synergistic effect[4]. With the patient's informed consent, camrelizumab 200 mg was administered intravenously on day 1 every three weeks (q3w) in combination with pyrotinib 400 mg orally once daily (qd). This regimen was delivered for seven cycles from January 2, 2022 to July 25, 2022. Following treatment, there was significant improvement in perianal swelling. Repeat CT examinations conducted on February 24, May 25, and July 28, 2022, demonstrated that the liver, lung, and primary tumour sites had reduced in size compared to previous assessments (Figure 2). Additionally, CEA levels decreased (Figure 3). Adverse reactions: Reactive capillary hyperplasia improved after laser treatment during the treatment period. Camrelizumab was temporarily discontinued in June 2022 due to intolerance. Additionally, the patient experienced diarrhoea.

Figure 2 Computed tomography imaging of the patient during therapy. A-D: Initial liver and lung metastases after chemotherapy were revealed by computed tomography on December 1, 2021; E-H: Computed tomography imaging on February 24, 2022, demonstrated reduced metastases in the liver and lung following two months of targeted therapy; I-L: Computed tomography imaging on May 25, 2022, showed a marked reduction in the size of lung lesions following five months of targeted therapy with programmed death 1 antibody and pyrotinib.

Figure 3 The change in carcinoembryonic antigen levels during treatment in a patient with advanced rectal cancer. CEA: Carcinoembryonic antigen.

Due to intolerance to capillary hyperplasia, the dosing regimen was adjusted. Sindilizumab 200 mg on day 1 q3w and pyrotinib 400 mg qd were administered four times on August 30, 2022, September 24, 2022, October 13, 2022, and November 4, 2022. During the fourth administration of sindilizumab, the patient experienced sudden onset of generalised urticaria. Symptoms were promptly treated with corticosteroids and resolved following treatment. CEA levels initially decreased but subsequently increased following treatment. A repeat CT examination on October 17, 2022 revealed that some lesions were slightly enlarged compared to their previous size.

Owing to the development of systemic urticaria during the last administration of sindilizumab, the medication regimen was adjusted. Tislelizumab 200 mg on day 1 q3w and pyrotinib 400 mg qd were administered four times on November 25, 2022, December 15, 2022, January 11, 2023, and February 2, 2023. Following treatment, CEA levels began to increase compared to pre-treatment levels, and anal cramping worsened. A repeat CT examination on January 11, 2023, indicated that the lesion was similar to the previous findings. Adverse effects included skin rashes and pruritus. To improve efficacy, tislelizumab in combination with pyrotinib and OXA was administered twice, on March 15, 2023, and April 5, 2023. Following this treatment, CEA levels decreased with partial relief of anal swelling. Adverse effects included rashes with pruritus, gastrointestinal reactions, and malaise.

DISCUSSION

Colorectal cancer is a common malignancy in China, and its incidence is increasing annually. Chemotherapy remains the standard treatment for patients with advanced colorectal cancer. Although targeted therapies provide survival benefits to patients with advanced metastatic colorectal cancer, most patients inevitably develop drug resistance. Small-molecule tyrosine kinase inhibitors such as regorafenib offer limited therapeutic benefits when used as third-line treatments[5,6]. In this case, the patient achieved stable disease as the best outcome following targeted combination chemotherapy, and the therapeutic agents demonstrated limited efficacy in refractory colorectal cancer.

With advancements in precision testing, the application of targeted therapies in clinical practice has increased, enabling more patients with tumours to benefit from precision medicine. It has been found that human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 2%-6% of colorectal cancers and 5%-14% of rat sarcoma viral oncogene homolog (RAS)/BRAF wild-type intestinal cancers[7,8]. HER2 amplification can lead to the formation of homodimers or heterodimers, which further autophosphorylate intracellular tyrosine residues, thereby activating receptor tyrosine kinases and initiating downstream signalling cascades. It has been suggested that HER2 overexpression correlates with tumour pathological features, including the primary site of the tumour and KRAS/BRAF/neuroblastoma rat sarcoma viral oncogene homolog oncogene homologue gene status. Additionally, HER2 overexpression may play a role in the growth, proliferation, and invasion of colorectal cancer[9]. Although there are currently no studies supporting the correlation between HER2 overexpression and the prognosis of intestinal cancer, HER2 overexpression can lead to resistance to anti-epidermal growth factor receptor monoclonal antibodies. Tumor regression after resistance can be achieved with anti-HER2 therapy[10,11]. The HER2-positive metastatic colorectal cancer study evaluated the use of trastuzumab plus lapatinib in patients with HER2-positive and wild-type RAS/BRAF advanced colorectal cancer who progressed after standard therapy[12]. The My Pathway study confirmed the benefits of a pertuzumab plus trastuzumab regimen in patients with HER2-amplified KRAS wild-type metastatic colorectal cancer[13]. Based on these studies, the 2021 edition of the National Comprehensive Cancer Network guidelines recommends trastuzumab plus pertuzumab or trastuzumab plus lapatinib for the third-line treatment of HER2-amplified advanced colorectal cancer. Emerging evidence suggests that cyclin-dependent kinase 12 functions as a novel regulator of tumour stem cells, promoting tumour initiation and contributing to anti-HER2 therapeutic resistance in human breast cancer[14]. Currently, limited data are available on anti-HER2-targeted therapies for HER2-amplified colorectal cancer in China.

Pyrotinib is a novel irreversible small-molecule tyrosine kinase inhibitor that inhibits the formation of HER family homodimers by targeting adenosine triphosphate-binding sites in the intracellular kinase domains of HER1, HER2, and HER4. This inhibition blocks the activation of downstream signalling pathways, thereby suppressing tumour cell growth[15]. It has been approved for use in patients with HER2-positive recurrent or metastatic breast cancer; however, its application in HER2-positive colorectal cancer remains underexplored. In our patient, the best response was stable disease with limited benefits during the application of standard first- and second-line therapies. The disease subsequently progressed but showed significant remission with the administration of pyrotinib. Some studies have suggested that anti-HER2 therapy can be initiated at an early stage in patients with HER2-amplified advanced metastatic colorectal cancer patients[16], but more clinical data are needed to substantiate its specific advantages.

Immunotherapy has demonstrated efficacy in the treatment of multiple tumours[17]. The KEYNOTE-164 study found that patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer benefited from pembrolizumab treatment, achieving a 1-year overall survival rate of 76% and 1-year progression-free survival rate of 41%[18]. Based on available data from international clinical studies and the 2021 edition of the National Comprehensive Cancer Network guidelines, it is recommended that patients with microsatellite instability-high/mismatch repair-deficient advanced colorectal cancer receive treatment with immune checkpoint inhibitors (ICIs). Studies have suggested that KRAS-mutant colorectal cancer derives limited benefits from immunotherapy, and the impact of HER2 expression status on immunotherapy efficacy remains unclear[4]. Emerging evidence indicates that patients harbouring tumour protein P53 mutations receive substantial clinical benefits from ICIs[19]. Immunotherapy and targeted therapy have synergistic effects in clinical oncology[20]. Small-molecule targeted drugs have been shown to activate specific cytotoxic T lymphocyte responses against tumour cells by inducing their death and the subsequent release of tumor-associated antigens. Antigen-presenting cells take up, process, and present antigens to T lymphocytes. Although a combination of ICIs targeting programmed death 1 (PD-1) and programmed death-ligand 1 can block tumour immune evasion, PD-1 antibodies, as ICIs, inhibit the PD-1/programmed death-ligand 1 signalling pathway by binding to PD-1 on T lymphocytes, thereby enhancing the anti-tumour efficacy of targeted therapies. This provides a compelling rationale for integrating immunotherapy with targeted therapy[21,22]. Immunotherapy and chemotherapy have synergistic effects. The combination of OXA and anti-PD-1 antibodies has been shown to yield superior outcomes compared to monotherapy, as OXA not only inhibits tumour growth and reduces transforming growth factor-β secretion but also enhances the antitumor immune response[23,24]. Studies have demonstrated that certain chemotherapeutic agents enhance anticancer immunity by inducing the release of immunostimulatory molecules from dying cancer cells or by exerting off-target effects on immune cell populations. Growing evidence supports the clinical value of combining appropriately administered chemotherapy with ICIs[25]. Furthermore, chemotherapeutic agents can enhance the function of effector cells by eliminating immunosuppressive cells, particularly when administered at sub-maximum tolerated dose[26-28].

In this case, the patient exhibited a minimal reduction in lesion size following multiple lines of targeted therapy and chemotherapy. The lesion progressively enlarges in the absence of an effective therapeutic intervention. Following treatment with an ICI in combination with pyrotinib, based on the results of precision medicine testing, the lesion exhibited significant shrinkage and a marked reduction in tumour marker compared to previous levels. This approach yields improved efficacy and symptom relief without serious, life-threatening adverse effects. During this period, various ICIs were altered due to intolerable cutaneous adverse reactions, including capillary naevus and generalised severe urticaria. The disease remained stable over a total treatment duration of 14 months. Subsequently, OXA monotherapy was initiated in response to progressive elevation of CEA levels and worsening symptoms. Although chemotherapy administered as monotherapy was less effective, a trend toward decreased CEA levels was observed following combination therapy. This effect may be attributed to synergistic interactions between the ICIs, pyrotinib, and OXA. The patient received this combination regimen twice and tolerated it well. Although this case represents an individual instance, it underscores the importance of precision diagnostics and individualized treatment strategies. It also highlights the potential of combining immunotherapy with targeted therapy and chemotherapy as well as the synergy among these modalities. However, further clinical research is needed to identify the optimal patient population for such combinations and determine the most effective sequence of drug administration.

CONCLUSION

We report a case of refractory colorectal cancer in which, despite the failure of conventional targeted therapy and chemotherapy, a precise individualized treatment plan was formulated based on genetic testing, resulting in significant clinical improvement.