A case report on the long-term survival of a patient with HER2-positive metastatic gastric adenocarcinoma and a short review of the current literature

First, the patient received a subtotal gastrectomy due to the suspected perforation and the lack of evidence of advanced disease in the computed tomography. Even though it was evident once the surgery began that he was in a locally advanced state, the gastrectomy was performed to treat the suspected perforation. Without the suspected perforation the treatment of choice would have been a perioperative chemotherapy regimen, with a neoadjuvant regimen of FLOT (leucovarin, 5‑fluorouracil, oxaliplatin, and docetaxel). This treatment regimen represents a quite novel treatment option, which showed promising results in a first-line perioperative setting [1]. This regimen can be considered as first-line therapy for patients with an excellent performance status. Furthermore, there were several trials to evaluate the role of HER2-targeted therapies in a first-line resectable setting of gastroesophageal adenocarcinoma; however, so far there have been no practice-changing results [2, 3].

The patient refused even adjuvant chemotherapy and only a few months later developed rapid recurrence with liver and lymph node metastases. This underlines the importance of adjuvant treatment particularly in advanced settings [4].

Due to the palliative state of the HER2-positive metastatic, gastric adenocarcinoma, a treatment according to the ToGA trial was administered [5]. Although this regimen provides a widely prolonged survival, the toxicities often lead to severe adverse events. Thus, several trials try to exchange cisplatin with oxaliplatin, seen as it has a more favorable toxicity profile [6]. However, so far no new treatment options for this setting are available. Also, other treatment strategies for HER2-positive gastric cancer have so far failed to improve the overall survival (OS) [7, 8].

After 6 cycles of therapy partial remission and an excellent performance score could be achieved; thus, trastuzumab maintenance therapy was established according to recently published observations [9‐11].

This maintenance was continued for 7 months, until there was a minor progression in lymph nodes metastases; however, stable disease concerning the liver metastases was evident. Thus, it was decided to treat the localized lymph node metastasis with radiotherapy and to expand the maintenance therapy with capecitabine. Radiation therapy of localized lymph node metastases is known to be effective as palliative treatment and to prolong OS [12, 13].

After 39 cycles of trastuzumab treatment, there was a progression with expansion of known liver and lymph node metastases as well as development of pulmonal metastases. Although trastuzumab proved to be very effective in our patient, we decided not to continue this treatment beyond progression. This decision was based on the results of a phase II study comparing the combination of paclitaxel beyond progression with trastuzumab versus paclitaxel alone, which showed that there was no benefit of combination therapy concerning OS [14]. Furthermore, other trials that targeted HER2 in a second-line strategy also failed to improve OS [15, 16]. It is surmised that this effect might be due to the loss of HER2 after first-line treatment [17].

Thus, we decided to further manage this patient as a HER2-negative case and applied the standard second-line chemotherapy with ramucirumab and paclitaxel [18]. A recent subgroup analysis of the initial trial also demonstrated efficacy benefits of this regimen after trastuzumab-based treatment [19]. However, the European Society of Medical Oncology—Magnitude of Clinical Benefit Scale (ESMO-MCBS), a score which indicates the substantial magnitude of clinical benefit of particular novel treatment options in oncology, is only 2 for ramucirumab and paclitaxel [20]. Thus, the clinical benefit for the patient might be minimal and that is why this regimen is critically viewed and widely discussed as a second-line option. However, our patient had a subjective benefit and good response throughout this therapy.

As a third line, we discussed to establish a therapy with trifluridin and tipiracil. This treatment option was published in 2018 and showed promising results on OS and quality of life when compared to placebo [21, 22]. Unfortunately, our patient died before this therapy regimen could be administered. The rapid deterioration after the surgery to reverse the colostomy was associated with rapid tumor progression. The cause for this rapid progression is not evident and might be due to the discontinuation of the antiangiogenic drug ramucirumab, the surgery itself [23], late knowledge of carcinomatosis due to low detection rates in CT scans [24] as well as other various unknown reasons.

Despite the success of modern chemotherapy, patients with metastatic gastric cancer continue to have a dismal outcome. The 5‑year relative survival for metastatic gastric cancer is 5.5% [25]. The median OS from therapy initiation until death was 13.9 months in HER2-positive patients in the ToGA trial. As mentioned above, this outcome represented a major breakthrough in modern oncology [26]. However, whether HER2-positivity is an independent prognostic marker is controversially discussed [27].

Furthermore, despite the fact that patients with peritoneal carcinomatosis with no measurable disease are known to have a significantly longer survival than that of patients with measurable disease (18.0 vs. 11.6 months), the median survival is still poor [28].

With regard to this data, the survival of our patient was exceptional. This might be due to the good performance status as well as the long treatment responses to first- and second-line therapy. Furthermore, individual treatment decisions which are made in interdisciplinary tumor boards might have contributed to this exceptional survival outcome as well. In addition, a favorable intrinsic biologic behavior of the tumor due to unknown mutations must also be considered. This underlines the importance of new prospective trials to further characterize and analyze gastric cancer cells.

Another important issue to discuss is the microsatellite instability (MSI). In 2017, the checkpoint inhibitor pembrolizumab was approved by the US Food and Drug Administration for the treatment of unresectable or metastatic MSI high solid tumors without any satisfactory alternative treatment options after at least one prior treatment [29]. Thus, pembrolizumab is a valid second and further line option for metastatic gastroesophageal tumors, which are MSI high. Unfortunately, the analysis of our patient’s tumor showed microsatellite stability and, thus, this treatment option was not possible.

Concerning future directions, novel anti-HER2 approaches and combinations are gaining attention. A recent phase II trial showed promising results with the antibody-drug conjugate trastuzumab deruxtecan as a third and further line strategy for patients with HER2-positive advanced gastric cancer [30]. This option is expected to be practice-changing within the next couple of years.

Another potential breakthrough was recently published in June 2020 and shows that pembrolizumab combined with trastuzumab and chemotherapy has promising activity in HER2-positive metastatic esophagogastric cancer in a first-line setting [31].