Management of HER2-positive and microsatellite instability-high advanced gastric cancer: a case report

Abstract

Chemotherapy for advanced gastric cancer has progressed significantly in the past few decades. Biomarker-specific drugs, including anti-human epidermal growth factor receptor 2 (HER2) drugs for HER2-positive patients and immune checkpoint inhibitors for those with microsatellite instability-high (MSI-H), have become common. However, patients who are positive for HER2 and have MSI-H are extremely rare, and there are no established treatments for these patients. We present the case of a 75-year-old, male patient with gastric cancer with lymph node metastases and liver infiltration. Biomarker analysis revealed HER2 3 + , loss of MLH1, and MSI-H. After three cycles of S-1, oxaliplatin, and trastuzumab, the primary tumor and metastases shrank markedly. He subsequently underwent gastrectomy and hepatectomy as conversion surgery, achieving a pathologically complete response. He has been recurrence-free for seven months postoperatively. The present case demonstrated the efficacy of trastuzumab-containing chemotherapy followed by conversion surgery in a patient with HER2-positive, MSI-H, advanced gastric cancer.

Introduction

Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor that controls cell proliferation and cell cycle signaling pathways [1]. Approximately one-fifth of patients with gastric/gastroesophageal junction (GEJ) cancer have overexpression or amplification of HER2 [2], and anti-HER2 treatments have demonstrated remarkable improvement in these patients [3, 4]. Numerous studies have reported the efficacy of immune checkpoint inhibitors (ICIs) against advanced gastric cancer [5–8]. In particular, cancers with microsatellite instability-high (MSI-H) are a molecularly defined subset associated with a high probability of responsiveness to ICI therapy [9]. However, the frequency of MSI-H in patients with gastric cancer is as low as 6.7% [10]. Furthermore, HER2-positive and MSI-H gastric cancer is extremely rare, with a reported incidence of approximately 0.7% [11]. For this rare subset of patients with HER2-positive and MSI-H unresectable advanced gastric cancer, the optimal treatment strategy—whether chemotherapy plus trastuzumab or chemotherapy plus immune checkpoint inhibitors—has not yet been established.

Conversion surgery utilizes preoperative therapy to “convert” unresectable tumors into resectable ones before removing them via surgical resection. This approach has garnered attention as potential means of improving the survival outcomes of patients with advanced gastric cancer. Several studies have demonstrated the efficacy of conversion surgery in treating advanced gastric cancer [12–14]. However, its benefit for patients with HER2-positive, MSI-H gastric cancer remains unconfirmed.

Herein, we report a case of HER2-positive, MSI-H gastric cancer in which a significant response was achieved using a trastuzumab-based chemotherapy regimen, followed by conversion surgery.

Case report

A 75-year-old, male patient presented with anorexia and weight loss. Upper gastrointestinal endoscopy revealed an ulcerative lesion in the antrum extending from the lower stomach (Fig. 1a). A biopsy of the lesion led to the diagnosis of adenocarcinoma. Computed tomography revealed that the primary tumor merged with enlarged hilar lymph nodes and infiltrated the S4 segment of the liver, appearing as a low-attenuation area (Fig. 2a, b). Additionally, one enlarged lymph nodes were observed along the lesser curvature of the stomach. These findings led to the diagnosis of stage IVA advanced gastric cancer (T4b(HEP)N1M0) according to the Union for International Cancer Control’s 8th edition criteria[15]. Immunohistochemical examination found HER2 3 + and loss of the MLH1 protein (Fig. 3), and MSI-H was confirmed using the MSI test kit (FALCO). Due to the extensive infiltration into the liver, the treatment plan was to precede with chemotherapy followed by surgery.

Fig. 1.

a Esophagogastroduodenoscopy before chemotherapy revealed an ulcerative lesion located in the antrum. b After the completion of three cycles of SOX + Tmab treatment, the primary lesion decreased significantly in the size, resulting in the formation of a white, lichenoid scar

Fig. 2.

Contrast-enhanced computed tomography. a, b Before chemotherapy (yellow arrows: primary tumor, hilar lymph nodes, and S4 segment of the liver were involved). c, d After three cycles of SOX + Tmab

Fig. 3.

a Hematoxylin and eosin-stained section demonstrating features of an intermediate to poorly differentiated adenocarcinoma. b HER2 staining intensity was scored at 3 + , indicating overexpression. c Negative MLH1 immunostaining, indicating mismatch repair deficiency

After three cycles of chemotherapy with S-1, oxaliplatin, and trastuzumab (SOX + Tmab), the primary tumor, associated lymph node metastases, and hepatic invasion shrank markedly (Figs. 1b, 2c, d). Serum tumor marker levels remained within normal ranges during the initial diagnosis and chemotherapy. The patient subsequently underwent a gastrectomy and hepatectomy as conversion surgery (Fig. 4), achieving a R0 resection with a pathologically complete response (Fig. 5). A transient elevation in tumor markers was observed postoperatively, followed by a declining trend. The patient resumed SOX + Tmab postoperatively. However, he had prolonged neutropenia and bacteremia, which appeared to be due to mucositis. Following a detailed discussion with the patient regarding the potential benefits and risks, the decision was made to discontinue postoperative chemotherapy. The patient was then placed under observation without any further treatment. At postoperative month 7, the patient was recurrence-free.

Fig. 4.

a Resected stomach demonstrating a scar from an ulcer at the tumor site (arrowhead). b Resected liver mass (30 × 20 × 10 mm) on the serosal surface (white arrow)

Fig. 5.

a Preoperative biopsy: hematoxylin and eosin-stained sections demonstrate features consistent with intermediate to poorly differentiated adenocarcinoma. b Postoperative analysis: examination of the resected gastric tissue reveals no evidence of viable tumor cells

Discussion

The patient in the present study, who had HER2-positive, MSI-H, advanced gastric cancer, responded favorably to a combination of chemotherapy and trastuzumab. MSI-H occurs much less frequently in HER2-positive cases (0.7%) than in gastric cancer in general, as demonstrated by the KEYNOTE-811 trial [11]. The extreme rarity of this condition may be attributable to the characteristics of HER2-positive tumors, which are typically associated with chromosomal instability and a low mutational burden [16, 17]. HER2 is anticipated to remain a crucial therapeutic target in the future. Novel approaches, including new antibody–drug conjugates and bispecific antibodies targeting this molecule, are currently undergoing clinical evaluation and show promise for integration into standard clinical practice (NCT03821233, NCT04276493). The KEYNOTE-811 trial demonstrated the efficacy of trastuzumab and pembrolizumab with chemotherapy in the treatment of HER2-positive gastric cancer [11], but this combination has not been tested against HER2-positive, MSI-H gastric cancer and has not been approved for use in Japan. While both anti-HER2 agents and ICIs have shown promise in their respective indications, direct comparisons of their efficacy in HER2-positive, MSI-H gastric cancers are currently lacking, highlighting an important area for future research. Further investigation is necessary to determine whether anti-HER2 agents or ICIs have a more potent antitumor effect when combined with chemotherapy if only one of these treatments are available.

Conversion surgery confers a significant survival benefit on patients with advanced gastric cancer particularly when preceded by effective chemotherapy and/or a targeted therapy regimen. The success of this approach is influenced by the biological characteristics of the tumor, its response to preoperative therapy, and the ability to achieve a R0 resection [14, 18]. As preoperative therapy, systemic chemotherapy with or without ICIs is effective [12–14, 19, 20]. For patients with HER2-positive gastric cancer, administering chemotherapy with trastuzumab preoperatively has proven to be beneficial [21]. Also, a previous study reported the efficacy of pembrolizumab followed by conversion surgery in a patient with MSI-H [22]. However, whether intensive chemotherapy, chemotherapy with ICIs or anti-HER2 therapy for HER2-positive cases is the optimal pre-conversion surgery regimen, is unclear. It is even more challenging to decide whether to use ICIs, anti-HER2 agents or a combination of these with chemotherapy as preoperative chemotherapy for MSI-H and HER2-positive cancer.

The present patient received a combination of trastuzumab and chemotherapy but did not receive any ICIs. The patient showed a highly favorable response, enabling conversion surgery to be performed, and a pathologically complete response was confirmed. MSI-H gastric cancers typically show reduced sensitivity to fluoropyrimidines [23]. In this case, strong HER2 expression (3+) may have enhanced trastuzumab’s efficacy [3], potentially offsetting the chemoresistance related to MSI-H. However, studies specifically comparing the efficacy of trastuzumab in MSI-H versus MSS gastric cancers are currently lacking. Given the potency of ICI therapy against MSI-H gastric cancer [9, 24, 25], an even better response might have been attained by the administration of additional ICIs. Moreover, the impressive survival outcome achieved in patients with MSI-H gastric cancer using nivolumab and ipilimumab in the CheckMate 649 trial suggested that incorporating ICIs into the chemotherapy regimen may obviate the need for surgical intervention [25].

There is, as of yet, no consensus on the efficacy of additional chemotherapy after conversion surgery. Some studies suggested that continuing chemotherapy postoperatively may confer additional benefits irrespective of HER2 status, and this approach is often used in clinical practice [26, 27]. However, there is no clear evidence of this treatment’s efficacy. Similarly, in the case of HER2-positive gastric cancer, there is no evidence verifying the efficacy of combining postoperative trastuzumab with chemotherapy. Moreover, MSI-H gastric cancer has a better outcome following surgery and benefits less from perioperative chemotherapy [23]. These findings indicate the lack of sufficient evidence and led to the discontinuation of postoperative chemotherapy in the present patient.

In conclusion, the present report is the first to describe the efficacy of systemic chemotherapy with trastuzumab followed by conversion surgery in a patient with HER2-positive, MSI-H, advanced gastric cancer. The present case highlights the need for further research into molecularly targeted treatments and surgical resection in this rare type of cancer.

Author contributions

TT and YK drafted the manuscript. TT, YK, SN, TO, YY, SM, MM, KE, KH, HO, SH, YS, HC, and TS participated in the patient’s treatment. All the authors have read and approved the final manuscript.

Funding

None.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

Haruhiko Cho has received lecture fees from Yakult Honsha outside of the submitted work.

Informed consent for publication

Informed consent was obtained from the patient for the publication of this report and the use of the accompanying images.

Human rights statement

This study was conducted in accordance with the Ethical Principles for Medical Research Involving Human Subjects as outlined in The Declaration of Helsinki.