Pembrolizumab response in stage IV luminal-type breast cancer with high microsatellite instability: a case report

Immune checkpoint inhibitors (ICIs) have recently revitalized cancer therapy. Pembrolizumab (PEM) has been approved to treat advanced or recurrent solid tumors with high microsatellite instability (MSI), which are refractory to standard chemotherapy regimens [1, 2]. The KEYNOTE-158 trial showed that PEM produced promising responses in tumors with high-frequency microsatellite instability (MSI-High) [3]. Studies have reported that the prevalence of MSI-High in breast cancers is approximately 0.5–1.7% [4]. Therefore, the use of PEM in patients with MSI-High breast cancer is not common.

The overall survival is considered good for bone metastases in breast cancer alone, even at stage IV [5]; however, we report a case of luminal-type breast cancer with exacerbating bone metastases in the short term, in which PEM was successfully used early in the disease course.

Her clinical course and treatments are summarized in Fig. 1. Postoperatively, after 3 months of docetaxel and cyclophosphamide therapy (4 courses) and 3 months of hormone therapy (tamoxifen), abdominal pain was observed. The cause of her abdominal pain is a 4-cm bone metastasis in the right iliac bone. The bone biopsy showed HR +, HER2 −, Ki-67 60%. Intensity-modulated radiation therapy (IMRT) was administered to the patient’s right iliac bone. Tamoxifen was discontinued, and a treatment using LH-RH agonist, fulvestrant, CDK4/6 inhibitor (Abemaciclib) and denosumab was initiated.

In the fifth month after bone metastases were known, metastasis was found in the lumbar spine and right 10th rib, and the treatment was deemed to be ineffective for progressive disease. Hormonal therapy was discontinued and replaced with the anticancer drug, Tegafur Gimeracil Oteracil Potassium (TS1) as it has no hair loss and is superior in quality of life.

One year after bone metastases were known, Magnetic Resonance Imaging (MRI) showed new metastases to the L2, L4 right, and left sacroiliac joints, right ilium, acetabulum, and nasal bone. The right iliac bone undergoing radiation therapy enlarged; the sacral tumor enlarged, and she developed metastatic para-aortic lymph nodes in Figs. 2a, 3a. Blood tests showed that tumor markers (CEA, CA15-3) were normal, but serum lactate dehydrogenase was abnormally high at 838 IU/L.

She used PEM as the 3rd treatment after recurrence. Her pelvic region was treated with IMRT for 2 weeks, and PEM (200 mg) was administered every 3 weeks with zoledronic acid. She was admitted to due to fever and malaise, but was recovered within a few days. Two months after PEM administration (after three courses of PEM), Diffusion-weighted Whole body Imaging with Background Suppression (DWIBS) revealed an overall increase in apparent diffusion coefficient values and shrinkage in tumor volume (Figs. 2b, 3b). The para-aortic lymph nodes also disappeared, opioid use was discontinued, and LDH levels trended downward. She was taken off OxyContin and returned to work.

Her treatment with PEM continued for one year with no exacerbation of metastases, the signal of the metastatic site on diffusion-weighted imaging remains low (Figs. 2c, 3c). She was able to keep her job, though, due to loss of appetite, treatment was stopped. We suspected we had missed some major lesion and decided to investigate its cause. This was two years after the bone metastasis was discovered. CT and colonoscopy showed no evidence of malignancy in the abdominal cavity. Gastroscopy revealed pyloric stenosis, she was put on prednisone, appetite returned, and so the diagnosis of irAE due to PEM was made. She was not diagnosed with Lynch syndrome, but a head MRI was performed to rule out brain tumors, which can be seen in Lynch syndrome [6]. Head MRI showed 4 brain metastases up to 1 cm in size, and gamma knife was performed. Fortunately, she is symptom free and has returned to work while taking aromatase inhibitors after 8 months of withdrawal of PEM (One year and 8 months after the start of PEM).

Although PEM has been approved for use in patients with MSI-High metastatic disease and no satisfactory alternative treatment, only five breast cancer patients were included in the KEYNOTE-158 trial, which included the largest cohort of non-colorectal MSI-High cancer, and breast cancer-specific response rates were not demonstrated [3]. In this case PEM was used as early as the third line of treatment for recurrence and was successful; in Luminal type recurrence, hormonal therapy is the mainstay and MSI measurements are often not considered early on. A PubMed search for MSI-High of Luminal type breast cancer patients with metastases treated with PEM was conducted. Vidula et al. [7] had a 245 days response in 5th line PEM treatment but used PEM for only 29 days in 10th line treatment. Kawamata et al. [8] used PEM in 5th line treatment of recurrence and had a 12 months response. Although less reported, measuring MSI early in the course of known metastasis and using PEM early in the course of disease may be worth considering if hormonal therapy is not successful.

If PEM has been successful in metastatic recurrence and there is clear imaging improvement, as in this case, we are not sure how long to continue treatment with PEM. The reasons are that PEM is expensive and we do not know when irAE will occur. The patient has reintegrated into the community, but should continue to be monitored for the development of irAE by monitoring blood tests and symptoms. Also, genetic testing to rule out Lynch syndrome has not been done because she refused [6] and will be reiterated.

We observe her treatment effect by imaging evaluation such as CT, DWIBS, and so on. Klouch et al. [9] to monitor treatment effect, reported that when the triple-negative breast cancer patient of MSI-High with metastases was given PEM and plasma microsatellites were measured, they were reduced and the patient’s general condition improved. If plasma levels of microsatellite instability correlate with the need for PEM, then the decision to continue treatment with PEM would be simpler and less expensive. Further research is awaited.

We have observed a positive therapeutic response after only three courses of PEM as the third-line treatment for recurrent luminal-type breast cancer with rapidly exacerbating bone metastases. She admitted to asymptomatic brain metastases but has returned to work. This case is an example of success with early introduction of PEM in MSI-High metastatic luminal-type breast cancer.