Pyrotinib monotherapy for advanced HER2-positive esophageal adenocarcinoma with trastuzumab resistance and chemotherapy intolerance: a case report and literature review

Abstract

HER2-positive advanced esophageal adenocarcinoma (EAC) cases demonstrate a poor prognosis because of drug resistance that develops after standard first-line trastuzumab therapy. The patient was initially diagnosed with stage cT2N1M0 III EAC. He underwent neoadjuvant chemotherapy, radical esophageal resection, and postoperative adjuvant radiotherapy. However, four months after treatment, the lesion relapsed and progressed to the right back, rendering the case inoperable. Pathological analysis revealed HER2 amplification. Given a poor tolerance to chemotherapy, the patient was administered cadonilimab and trastuzumab for three months. Subsequently, the second-line therapy was switched to pyrotinib monotherapy as a salvage treatment. Remarkably, after one month of treatment, the tumor showed significant reduction, with mild toxic side effects. Pyrotinib can be used for salvage later-line therapy in HER2-positive advanced EAC with trastuzumab resistance or poor chemotherapy tolerance, which deserves further promotion.

Introduction

Esophageal adenocarcinoma (EAC) is a malignancy of the gastrointestinal tract, whose incidence is steadily increasing in the aging population, with a higher prevalence in men compared with women [1]. Predominantly (> 90%) located in the lower esophagus, close to the Gastroesophageal Junction (GEJ), EAC lacks features distinguishing it from gastric adenocarcinoma [2, 3]. Because clinical symptoms often manifest late, most EAC cases are diagnosed at an advanced stage [4]. Despite an improvement in the 5-year survival rate of advanced EAC patients to approximately 20% over the past two decades, this rate remains suboptimal compared to other tumor types [5].

The status of HER2 amplification plays a critical role in designing a comprehensive treatment approach for advanced EAC and GEJ adenocarcinoma [6]. Retrospective studies have demonstrated a significant correlation between HER2 amplification and EAC prognosis [7].

Currently, trastuzumab is the only clinically proven and effective anti-HER2 drug available for the treatment of HER2-positive EAC [8]. However, 30% to 60% patients with advanced HER2-positive gastric or GEJ cancer lose HER2 expression following first-line chemotherapy or trastuzumab treatment, several guidelines recommend discontinuing anti-HER2 treatment in trastuzumab-resistant HER2-positive EAC cases [9–11].

Pyrotinib, a small-molecule, irreversible pan-ErbB receptor tyrosine kinase inhibitor [12], has shown promising effects in multiple studies. The National Comprehensive Cancer Network (NCCN) guidelines explicitly recommend this drug as a second-line treatment option for recurrent or metastatic HER2-positive breast cancer cases, including those resistant to standard trastuzumab and/or pertuzumab. According to the latest guidelines, pyrotinib can be administered either alone or in combination with trastuzumab in neoadjuvant therapy or as a first-line treatment of advanced HER2-positive breast cancer [13–15].

In addition, a phase I study of pyrotinib combined with camrelizumab and chemotherapy for first-line treatment of advanced gastric cancer also reported promising data [16].

This case report describes a patient with HER2-positive recurrent EAC who could not tolerate chemotherapy and had no response to anti-HER2 standard regimen combined with PD-1/CTLA-4 bispecific antibody. The continuation of anti-HER2 treatment with pyrotinib resulted in an incredible remission of local lesions, and the patient showed good tolerance to pyrotinib during the treatment.

Case description

A 62-year-old male with a 40-year history of smoking and drinking was admitted to a local hospital in July 2022 for persistent dysphagia, hematochezia, and hematemesis in the preceding 16 months. His medical history included a 4-year diagnosis of hepatitis C (confirmed by a hepatitis C virus antibody titer of 13.04 U/ml on July 13, 2022), a 10-year history of hypertension, and a 4-year history of type 2 diabetes. Physical examination revealed no notable enlargement of supraclavicular lymph nodes. Upon admission, routine serum analysis showed an elevated alpha-fetoprotein (AFP) level of 565.5 ng/mL. Imaging techniques, including chest computed tomography (CT) and X-rays, demonstrated significant thickening and stricture of the esophageal lumen adjacent to the cardia, suggestive of esophageal tumors. Additionally, enhanced CT detected lymph nodes in the right mediastinum near the lower esophagus, with a maximum long diameter of 4.4 cm. Esophageal endoscopy further confirmed these findings, revealing occupied esophagus and cardia. The upper margin of the tumor was approximately 35 cm from the incisors, while the lower margin extended close to the cardia. Biopsy samples obtained during endoscopy confirmed the diagnosis of adenocarcinoma. Enhanced chest and abdominal CT showed no evidence of distant metastasis. Based on the American Joint Committee on Cancer (AJCC) non-operative staging for esophageal cancer (2009 edition), the case was cT2N1M0 (stage III) [17], and 4 cycles of SOX perioperative chemotherapy and radical surgery were scheduled per NCCN guidelines [18].

After two cycles of neoadjuvant therapy consisting of oxaliplatin (130 mg/m² d1/Q21d) combined with S-1 (60 mg, 2/d, d1-14/Q21d), the patient exhibited a progressive disease (PD) of the esophageal lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Meanwhile, the patient developed a Grade 4 nausea, accompanied by mild upper gastrointestinal reaction including bloating, belching and dyspepsia, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The mild symptoms showed remission after short period of oral administration of digestive enzymes and omeprazole. While antiemetic drugs were administered for nausea, including tropisetron, metoclopramide, dexamethasone, and aprepitant, the nausea was not effectively controlled, leading to intolerance for further chemotherapy.

Before surgery on September 3, 2022, AFP levels rose to over 2000 U/mL. Contrast-enhanced CT of the chest revealed an increased soft tissue shadow volume in the posterior mediastinum. Prechemotherapy and preoperative CT scans are shown in Fig. 1, No further chemotherapy or radiotherapy was administered before surgery.

Fig. 1.

Prechemotherapy and preoperative CT scans, conducted at the local hospital, depicting response in right mediastinum mass near the lower esophagus (indicated by arrows). A Jul. 2022, prior to chemotherapy. B Sep. 2022, after 2 cycles SOX and prior to surgery

In September 2022, the patient underwent an Ivor-Lewis esophagectomy with secondary lymph node dissection for esophageal cancer, followed by gastric tube reconstruction. Totally 27 lymph nodes were harvested, achieving an R0 resection, and postoperative recovery progressed smoothly. Postoperative pathological analysis confirmed a 3 tumor regression grade score and the presence of an AFP-producing cancer (moderately to poorly differentiated adenocarcinoma) located in the lower esophagus near the cardia, with metastasis detected among the lesser curvature nodes (1/20). Immunohistochemical analysis revealed HER2 (2+), AFP (+), MLH1 (+), PMS2 (+), MSH6 (+), and MSH2 (+). Based on the above findings, the patient was diagnosed with primary EAC. According to the NCCN esophageal cancer staging system (8th version) [19], the case was classified as ypT3N1M0G2 (stage IIIB).

In November 2022, the patient underwent local prophylactic radiotherapy (46 Gy/23 fractions) targeting the tumor bed, lymph node metastasis, and the lymph node drainage area, in combination with oral capecitabine. Radiation doses to organs at risk remained within acceptable limits.

After radiotherapy, no additional treatments were administered. However, in March 2023, the patient presented to a local hospital because of a painful mass on his back. Physical examination revealed a right back mass measuring 8 cm × 7 cm, which was hard, poorly mobile, and tender, suggesting potential tumor recurrence. However, the patient declined further medical analyses, such as serum tumor marker detection, CT and endoscopy, and instead chose to receive herbal treatment for two months, which proved ineffective.

In May 2023, the patient was referred to our department for severe pain, scoring 9 on the Numerical Rating Scale (NRS, 0–10 version). Upon admission, chest CT revealed a new lesion on the back, indicating progressive disease (PD). Genetic testing by fluorescence in-situ hybridization (FISH) and next-generation sequencing (NGS) performed by AmoyDx Biotechnology Co. Ltd. (Xiamen, China) revealed no HER2 gene mutation and a ratio of 5.1 of HER2:CEP17, indicating the amplified HER2 gene. Additionally, a positive expression of programmed cell death ligand 1 (PD-L1) was detected, with a 3 combined positive score (CPS) using E1L3N assays with Leica Bond-Max automated biosystem. Following multidisciplinary consultations, the patient was prescribed first-line treatment with trastuzumab (initial load of 480 mg d1/Q21d, 360 mg from the second cycle) combined with cadonilizumab (360 mg d1/Q14d) starting in May 2023. However, the patient declined concurrent chemotherapy due to concerns about potential side effects.

In July 2023, after the first treatment cycle, the patient reported significant pain relief. However, CT revealed no reduction in the dorsal lesion. Subsequently, the patient experienced intermittent grade 1–2 diarrhea during the treatment, which resolved spontaneously. By September 2023, the patient had worsened back pain and progressive dysphagia, prompting 2-week follow-up intervals. Chest CT indicated local focal progression, and the patient had a 4-month period of stable disease (SD).

After providing signed informed consent, the patient commenced maintenance therapy with pyrotinib at a dose of 320 mg/d in September 2023. One month post-therapy, enhanced chest CT demonstrated a PR in both neck and dorsal lesions.

After one month of pyrotinib therapy, the patient developed persistent grade 3 diarrhea. Consequently, the condition was effectively managed by reducing the dose of pyrotinib to 240 mg/d and administering glucocorticoids for their anti-inflammatory effects. Two weeks later, pyrotinib was successfully re-administered at the original dose of 320 mg/d, which was well tolerated by the patient.

Until March 2024, chest CT indicated no local lesion progression. The entire treatment process, the changes of the dorsal lesion, the corresponding changes in CT findings, and changes in AFP levels are shown in Figs. 2, 3, 4, 5, 6.

Fig. 2.

Treatment process and disease development. A SOX 2 cycles, then developed a PD. B Radical esophageal resection in September 2022. C Postoperative adjuvant radiotherapy combined with capecitabine from November 2022. D Herbal treatment from March 2023 for 2 months. E Cadonilimab and trastuzumab therapy in our department. F Pyrotinib therapy, with a PFS of 7 months. PR partial response, CR complete response, PD progressive disease, SD Stable Disease, PFS progression-free survival, SOX oxaliplatin + tegafur

Fig. 3.

Changes of the dorsal lesion. A Dorsal lesion in May 2023; B Dorsal lesion reduction after one month of pyrotinib therapy in Oct. 2023

Fig. 4.

Chest CT scans depicting response in right dorsal mass (indicated by arrows) to the trastuzumab + cadonilizumab combination regimen and subsequent pyrotinib therapy. A May 2023, prior to combination treatment. B Jul. 2023, after 1 cycle of treatment with the combination regimen. C Sep. 2023, after 6 cycles of treatment with the combination regimen. D Oct. 2023, after 1 month of pyrotinib therapy. E Jan. 2024, after 5 months of pyrotinib therapy. F Mar. 2024, after 7 months of pyrotinib therapy. CT, computed tomography

Fig. 5.

Chest CT scans depicting response in right neck mass (indicated by arrows) to the trastuzumab + cadonilizumab combination regimen and subsequent pyrotinib therapy. A May 2023, prior to the combination treatment. B Jul. 2023, after 1 cycle of treatment with the combination regimen. C Sep. 2023, after 6 cycles of treatment with the combination regimen. D Oct. 2023, after 1 month of pyrotinib therapy; E Jan. 2024, after 5 months of pyrotinib therapy. F Mar. 2024, after 7 months of pyrotinib therapy. CT computed tomography

Fig. 6.

Changes in alpha-fetoprotein (AFP) (ng/mL) levels during the whole treatment

At the submission of this case report, the patient had survived for over 11 months, and treatment with pyrotinib is currently ongoing, with a progression-free survival (PFS) exceeding 7 months.

Discussion

AFP-producing EAC is extremely rare and may demonstrate resistance to chemotherapy as the AFP-producing gastric cancers [20–23]. The values of AFP for this case noticeably decreased as the treatment progressed, suggesting that the prognosis for the patient may be related to AFP. We also screened for other tumor markers, such as CA 19–9, CA 15–3, CA 12–5, and CEA in Table 1, and noted slight fluctuations within the reference range.

Table 1.

The changes in relevant tumor markers throughout the treatment process

Items	2022-07-13	2022-09-03	2023-05-25	2023-10-27	2023-12-12	2024-01-30	2024-02-29	2024-04-09
AFP (ng/ml)(< 7.0)	565.5	2000 +	NA	247.2	7.4	24.2	30.7	19.4
CEA (ng/ml)(< 5.0)	1.2	2.5	4.1	2.6	3.2	4.8	3.0	2.1
CA15-3 (U/ml)(< 20.0)	NA	NA	19.5	NA	NA	23.2	22.8	17.2
CA12-5 (U/ml)(< 24.0)	15.0	48.6	10.3	NA	33.9	44.3	NA	NA
CA19-9 (U/ml)(< 30.0)	14.9	3.2	12.9	11.8	18.1	NA	NA	NA

AFP Alpha-Fetoprotein, CEA carcinoembryonic antigen, CA15-3 Cancer Antigen 15–3; CA12-5 Cancer Antigen 12–5, CA19-9, Cancer Antigen 19–9

Approximately 30% of EAC cases are HER2-positive, and currently, targeting this locus represents the only targeted therapy with clear evidence of efficacy in EAC, besides antiangiogenic drugs [24]. Even though epidermal growth factor receptor (EGFR) is overexpressed in 90% of esophageal cancer cases, anti-EGFR treatments have conferred no improvement in survival rates [25].

Trastuzumab is the sole drug available for anti-HER2 therapy in HER2-positive EAC, backed by definitive clinical evidence and proven efficacy. The ToGA study established trastuzumab combined with chemotherapy as a first-line treatment option for HER2-positive EAC [8]. The results indicated enhanced prognosis in the experimental group administered trastuzumab targeting the HER2 locus alongside standard chemotherapy. Specifically, median overall survival (mOS) and median progression-free survival (mPFS) in the experimental group increased significantly from 11 months to 13.8 months and from 5.5 months to 6.7 months, respectively.

With the rapid development of tumor immune checkpoint inhibitors, immunotherapy for EAC has progressed substantially. EAC of the MSI-H subtype is highly likely to respond to PD-1 receptor immunotherapy [26]. The NCCN guidelines recommend first-line immunotherapy, either alone or in combination with chemotherapy, for MSI-H/dMMR and HER2-negative EAC. Currently, the Food and Drug Administration (FDA) has approved pembrolizumab in combination with trastuzumab and chemotherapy containing fluoropyrimidine and platinum for the first-line treatment of locally advanced, unresectable, or metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma [27].

However, in the current case, immunohistochemical analysis indicated that MLH-1, PMS-2, MSH-6, and MSH-2 were all positive, and the CPS was low. This suggests that the benefit conferred by immunotherapy may not be as significant as expected. Nevertheless, a low CPS does not preclude some benefit from immunotherapy. This simply implies that the response may not be as dramatic as in cases with a higher CPS.

HER2-positive tumors typically feature chromosome instability and lower tumor mutation burden (TMB)[28]. In the KEYNOTE-811 study [27], only three participants (0.7%) in the target group had MSI-H status, while an objective remission rate (ORR) of 74.4% was detected among all patients.

Furthermore, in patients with low PD-1/L1 scores across various tumor types, inhibitors combining PD-1 or PD-L1 with CTLA-4 can significantly improve efficacy [29–32]. In the CheckMate-649 study [33], the treatment regimen of nivolumab plus ipilimumab demonstrated a significant advantage in mDOR versus chemotherapy in individuals with a CPS score below 5. Additionally, the FDA has approved the combination of nivolumab and ipilimumab, targeting PD-1 and CTLA-4, respectively, for the treatment of esophageal cancer.

Cadonilimab blocks the interactions of both PD-1 and CTLA-4 receptors with their respective ligands, namely PD-L1/PD-L2 and B7.1/B7.2. By inhibiting these interactions, cadonilimab promotes tumor-specific T-cell immune activation, exerting antitumor effects [34].

Compared with the nivolumab plus ipilimumab regimen, the cadonilimab regimen demonstrated more significant advantages in terms of ORR and treatment-emergent adverse events (TEAEs) in a multicenter cohort study of esophageal squamous cell carcinoma [35]. This suggests that cadonilimab may provide a more effective and better tolerated treatment option for certain cancer cases. Cadonilimab has been approved by the National Medical Products Administration (NMPA) for the treatment of recurrent or metastatic cervical cancer cases with previously failed platinum-containing chemotherapy. This approval was based on the drug's ability to improve the outcomes of these patients. Furthermore, in the AK104-302 study [36], cadonilimab showed impressive results in G/GEJ adenocarcinoma cases with a CPS score below 5, with an ORR of 68.2%, a disease control rate (DCR) of 100%, and an mPFS of 7.5 months. These findings indicate that cadonilimab is a promising treatment option for this patient population. Recently, cadonilimab combined with oxaliplatin and capecitabine (XELOX) was approved for first-line treatment of unresectable locally advanced, recurrent, or metastatic G/GEJ adenocarcinoma. This combination therapy may provide an additional effective treatment option.

The described case involved a complex treatment journey for a patient with HER2-positive EAC. Initially, the patient underwent radical surgery and perioperative chemoradiotherapy but developed intolerable adverse reactions during chemotherapy, leading to a decline of subsequent chemotherapy by the patient. First-line chemotherapy did not achieve the desired remission, and combined therapy with cadonilimab and trastuzumab was attempted to compensate for the loss of potential efficacy because of chemotherapy intolerance. However, this approach did not yield the expected results despite the possible synergistic effects of HER2 and PD-1 inhibition reported by numerous studies [37–41], as indicated by contrast-enhanced CT showing local lesion progression.

Resistance to trastuzumab and its unclear mechanism pose significant challenges in the treatment of HER2-positive EAC. In China, anti-HER2 therapy is typically discontinued after resistance occurs, and single-agent chemotherapy is often recommended per CSCO guidelines. The NCCN guidelines suggest replacing regimen containing ramucirumab or continuing anti-HER2 therapy with trastuzumab deruxtecan, both of the above options are of limited availability in China.

Pyrotinib, a small molecule tyrosine kinase inhibitor, has a different mechanism of action than trastuzumab. Trastuzumab binds to the extracellular domain to inhibit HER2, and the resistance mechanism may involve HER2 mutation or heterodimerization with other receptors [42]. Pyrotinib covalently interacts with ATP binding sites in intracellular kinases such as EGFR/HER1, HER2 and HER4, then completely blocks the downstream pathway activated by HER family homodimers or heterodimers on tumor cell membrane. This suggests that pyrotinib can overcome trastuzumab resistance by targeting multiple ErbB receptors and their mutated forms [12]. In contrast to trastuzumab, pyrotinib acts on the intracellular pathway and is more effective for advanced breast cancer cases with brain metastasis because of its capacity of crossing the blood–brain barrier [15]. In addition, a study by Lian et al. showed that pyrotinib may inhibit the proliferation of human EAC cells and enhance the sensitivity of tumor cells to radiotherapy by inhibiting HER2 phosphorylation, modulating cell cycle distribution, and regulating DNA repair-related proteins [43]. These findings jointly suggest a clinical approach for pyrotinib in EAC treatment.

Diarrhea is the most prevalent side effect of pyrotinib. In the PHENIX and PHOEBE studies, approximately 95% of cases had diarrhea of all grades, with about 30% experiencing grade 3 or higher diarrhea [13, 14]. Meanwhile, in a study conducted by Li et al., 48.8% of cases developed grade 3 TEAEs [16]. Despite prophylactic diarrhea management, persistent grade 3 diarrhea still occurred during follow-up treatment in the current case. We promptly managed the symptoms through dose reduction and the administration of prescribed symptomatic medications.

Based on the distinct mechanisms of trastuzumab and pyrotinib, combination of pyrotinib and capecitabine has demonstrated remarkable efficacy in HER2-positive advanced breast cancer patients. Encouraging results have also been reported by preclinical and clinical studies of pyrotinib in EAC. Fortunately, we had an opportunity to break the shackles of conventional guidelines. We attempted to administer pyrotinib monotherapy as a continuation of second-line anti-HER2 therapy due to disease progression after the first-line trastuzumab-based chemotherapy regimen. This approach has proven beneficial for the survival of this patient thus far. If the current standard anti-HER2 treatment had been applied, the patient might not have achieved a PR. The continued effectiveness of anti-HER2 therapy suggests a crucial role for the HER2 pathway in the progression of this case.

Compared with the single-agent chemotherapy regimen for EAC, the standard second-line treatment of ramucirumab plus paclitaxel significantly improved mPFS from 2.9 months to 4.4 months and mOS from 7.4 months to 9.6 months [44]. Additionally, a mOS of 5.2 months was observed in ramucirumab monotherapy group [45]. In patients with trastuzumab-resistant HER2-overexpressing EAC, maintaining second-line anti-HER2 therapy with trastuzumab deruxtecan resulted in a PFS of 5.6 months and an mOS of 12.5 months [46]. The present case demonstrated an exceed-7-month period of PFS, which is likely better than that of the regimen prementioned. Furthermore, the safety profile of pyrotinib was more acceptable in this patient compared with that of the previously administered chemotherapy.

Limitations arise equally from the fact that HER2 status often changes after the use of trastuzumab, and acquired resistance is likely attributed to this change. Post-line anti-HER2 therapy necessitates a re-evaluation of HER2 status to ascertain whether HER2 loss has occurred after first-line chemotherapy or trastuzumab treatment. Based on this, we recommend that the patient have a puncture to obtain a specimen for HER2 testing before the prescription of pyrotinib. However, the patient declined additional pathological testing.

Given the successful outcome in this case and the unique mechanism of pyrotinib, it is conceivable that pyrotinib could potentially be used as a continuous anti-HER2 salvage therapy after resistance to standard anti-HER2 regimens. However, this hypothesis needs to be confirmed in large-scale clinical studies, which could provide valuable insights into the efficacy and safety of pyrotinib as a salvage therapy and help establish its role in the treatment of HER2-positive cancers.

Conclusion

This case report presents a patient with advanced esophageal adenocarcinoma (EAC) with resistance to trastuzumab combined with cadonilimab. Despite this resistance, the case responded favorably to second-line monotherapy with the anti-HER2 agent pyrotinib, achieving an incredible clinical outcome and good tolerability. This study provides compelling evidence that pyrotinib is a promising treatment option for HER2-positive EAC. However, further prospective clinical trials are warranted to confirm these findings and establish definitive recommendations for pyrotinib use. The encouraging results observed in this case underscore the potential of pyrotinib as a valuable therapeutic agent for the management of HER2-positive EAC.

Author contributions

TW drafted the manuscript and followed up the patient. MYH contributed to data analysis and revised the manuscript. WG collected the clinical data. All authors made substantial contributions to the conception of this work and approved the submitted version.

Funding

Not applicable.

Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Declarations

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committees of China-Japan Union Hospital of Jilin University. All methods were carried out in accordance with the Declaration of Helsinki guidelines.The clinical data were presented anonymously. Informed consent statement for case reporting and publishing was obtained from the participants and their families.

Consent for publication

Written informed consent was obtained for the publication of this case report and any accompanying images.

Competing interests

The authors declare no competing interests.