Treatment patterns and clinical outcomes in patients with metastatic triple-negative breast cancer: a large-scale data analysis using the Japanese claims database

Triple-negative breast cancer (TNBC), defined by the lack of tumor cell expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2, HER2 [1], accounts for approximately 15% of invasive breast cancers [2‐4] and is associated with aggressive tumor biology and poor prognosis. An observational cohort study in Japan reported 13.4 and 12.7 months as the median overall survival (OS) in patients with locally advanced or metastatic TNBC (mTNBC) receiving first- and second-line therapy, respectively [5]. The result of the study suggests that there is a high unmet medical need for Japanese patients with mTNBC.

Chemotherapy has been the main treatment for mTNBC. As first-line treatment options for mTNBC, some agents have recently been approved such as programmed death-1 (PD-1) inhibitors in combination with chemotherapy and poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPis) monotherapy in Japan. According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) [6], combination therapy with pembrolizumab is recommended as the first-line treatment in patients with PD-L1-positive mTNBC regardless of germline breast cancer susceptibility gene (BRCA) mutation status. Similarly, PARPis and platinum-based chemotherapy are the preferred regimens in patients with PD-L1-negative and germline BRCA1/2-mutated mTNBC, while systemic chemotherapy is recommended in patients with PD-L1-negative and germline BRCA1/2-wildtype mTNBC. As for the second-line treatment, PARPis are the preferred regimens in patients with germline BRCA1/2-mutated mTNBC. Systemic chemotherapy or sacituzumab govitecan is recommended for treatment regardless of any subtype of mTNBC. Sacituzumab govitecan is approved for second-line and later treatment of mTNBC in multiple countries [7]. Fam-trastuzumab deruxtecan-nxki is recommended as second-line therapy in patients with germline BRCA1/2-wildtype and hormone receptor (HR)-negative and HER2 immunohistochemistry (IHC) 1+ or 2+/in situ hybridization (ISH) negative mBC. As third-line therapy and beyond, systemic chemotherapy and targeted agents based on specific genetic mutations are recommended. In the European Society for Medical Oncology (ESMO) guidelines [8], chemotherapy in combination with an immune checkpoint inhibitor (ICI) is recommended as first-line therapy in patients with PD-L1-positive mTNBC. Approximately 40% of patients with TNBC possess PD-L1-positive tumors [9]. Similarly, olaparib and talazoparib are recommended in patients with PD-L1-negative and BRCA1/2-mutated mTNBC, while taxane monotherapy is recommended as the preferred option in patients with PD-L1-negative and BRCA 1/2-wildtype mTNBC. The guidelines have also recommended sacituzumab as the preferred treatment option for second-line treatment; after progression, all chemotherapy recommendations for HER2− disease also apply for TNBC, such as eribulin, capecitabine, and vinorelbine. In the Japanese Breast Cancer Society Clinical Practice Guideline [10], ICI plus chemotherapy for patients with PD-L1-positive mTNBC have been recommended as first-line therapy. If anthracyclines or taxanes have not been used in perioperative chemotherapy, the standard of care is to administer anthracyclines or taxanes as first-line or second-line chemotherapy for HER2-negative metastatic breast cancer (mBC), respectively. The Japanese guidelines also recommend PARPis as treatment options for patients with BRCA1/2-mutated, HER2-negative mTNBC who have previously been treated with chemotherapy, and single-agent chemotherapy for patients with PD-L1-negative, BRCA1/2-wildtype mBC. Although ICIs and PARPis have expanded the treatment options for patients of certain subtypes or those having certain biomarkers, chemotherapy remains the standard of care for most patients with mTNBC, and there is a need for therapeutic advances in mTNBC.

Although limited treatment options and poor prognoses for mTNBC have been reported [11], evidence regarding the real-world effectiveness of each line of therapy is limited, particularly in Japan.

In a Japanese observational study in the clinical setting, combination chemotherapy in the first line of treatment showed a higher overall response rate (62.2% for first line vs. 45.1% for second line) and longer progression-free survival (PFS, 9.3 months for first line vs 7.2 months for second line) compared to those showed in the second line of treatment in patients with mTNBC, thereby indicating the importance of optimal treatment choice in each line for patients with mTNBC [5].

Given mTNBC’s aggressive nature, poor prognosis, and limited treatment options, it is important to understand the real-world effectiveness and safety of treatment regimens and patient characteristics.

Therefore, this study evaluated the treatment patterns, time to next treatment or death (TTNTD), time to treatment discontinuation (TTD), adverse events (AEs) of interest, and medical costs among patients with mTNBC in real-world healthcare settings using the Japanese medical claims database.

This study provides the first evidence from a multicenter assessment of real-world treatment patterns and outcomes among patients with mTNBC in Japan. Few reports have investigated the treatment patterns for mTNBC in clinical practice in Japan. In Taiwan, the majority of mTNBC patients receive combination therapy as first-line treatment [13]. In contrast, approximately 65% of the patients with mTNBC received monotherapy as the first-line therapy in this study, indicating the proportion of patients who receive monotherapy as first-line therapy for mTNBC in Japan is similar to that in western countries [14, 15].

In this study, 2236 patients with mTNBC were included in the first-line cohort. At the level of individual regimens, capecitabine and S-1 monotherapy were the two most common regimens in first-line treatment, while 20% of patients were treated with anthracycline-containing regimens and 30% were treated with taxane-containing regimens.

Regarding treatment patterns by the presence or absence of perioperative therapy, < 5% of patients with history of perioperative therapy were treated with anthracycline in the first-line treatment; in contrast, approximately one-third of the patients with no history of perioperative therapy were using anthracyclines. According to the Japanese guideline [10], anthracycline regimens are recommended as first- or second-line chemotherapy if they have not been used in perioperative chemotherapy. Hence, the study results suggest that patients were treated with anthracycline regimen in perioperative chemotherapy and may not be eligible for anthracycline regimen in metastatic setting.

In this study, the two most common regimens in the first-line therapy were capecitabine and S-1. These regimens are weakly recommended as first-line treatment in breast cancer clinical practice guidelines. An overseas study showed that cisplatin combined with nab-paclitaxel or paclitaxel is the preferred first-line treatment for mTNBC [16]. This difference between Japan and other countries in the commonly used regimen is most likely due to the difference in the treatments covered by insurance. In this study, eribulin was also the most used drug in the second- and third-line cohorts. Eribulin was shown to prolong OS more than did capecitabine in the second- and later-line setting and is recommended in the guideline for patients treated with anthracyclines and taxanes [17]. Regarding age-specific treatment patterns, S-1 was used more frequently in patients aged ≥ 65 years as the first-line treatment than in those aged < 65 years. S-1 is an oral fluoropyrimidine agent consisting of tegafur (a prodrug of fluorouracil), gimeracil, and oteracil, which is approved for treatment of various cancer types and widely used in Japan [18]. The study showed S-1 has a low incidence of myelosuppression-induced side effects, such as neutropenia. Considering the less frequent AEs of S-1, safety profile might be one of the reasons for treatment choice for older patient.

Regarding the TTNTD, the length decreased with advancement in the line of treatment. Given that TTNTD is often used as a surrogate endpoint for PFS in real-world data, these results are similar to the prospective observational study of bevacizumab combined with paclitaxel in patients with locally advanced or metastatic TNBC, where the median PFS was 9.3 months in the first-line cohort and 7.2 months in the second-line cohort, respectively [5]. However, there was no difference between the lines of treatment regarding the TTD. This suggests that, although there is no change in treatment tolerability in the different lines, the treatment effect seems to weaken as the line progresses.

For AEs of interest, the proportions of nausea/vomiting, neutropenia/leukopenia, and febrile neutropenia in “other regimens” were much lower than those in the anthracycline-containing regimens. This was considered to be one of the reasons that capecitabine and S-1 were the commonly used regimens as the first-line therapy, especially in older patients.

Regarding medical expenses, there was a tendency for costs to increase toward the later lines. As the therapy progresses, the usage rate of relatively inexpensive regimens (doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, capecitabine, S-1) decreased, while the usage rate of relatively expensive regimens (bevacizumab/paclitaxel, atezolizumab/nab-paclitaxel, eribulin) increased (usage rates were calculated using the patient population included in each cohort as the denominator) contributing to the increase in medical costs as the treatment course progresses. Although public health insurance covers most medical expenses in Japan, long-term treatment costs affect patients’ lives. Thus, treatment costs are a major concern for patients with breast cancer, especially in later line of treatment. The cost effectiveness of each sequence should be further investigated to support the treatment strategy.

Based on the observation collected, the treatment for mTNBC was selected generally according to the treatment guideline in clinical practice in Japan. However, some patients were treated with chemotherapy regimen with low recommendation level. In addition, late-line treatments tend to be less effective and increase the burden of medical expenses. It suggests a high unmet medical need for new treatment options; thus, better risk–benefit profile is necessary.

This study was based on health insurance claims and DPC data. Therefore, some limitations should be considered. Due to the absence of biomarker data for ER, PR, and HER2, patients with TNBC were identified by the absence of hormonal therapy and anti-HER2 drugs. Patients with other breast cancer subtypes may have been included in the study population. HER2 expression has been reported to change during treatment; however, this was not considered in our study because it was not captured in the database. In addition, there may be off-label use of some drugs for breast cancer in Japan. Moreover, owing to unmeasured confounding factors, the possibility of residual confounders cannot be ruled out. Another limitation was that the MDV database has no data of performance status or stage. Therefore, we could not consider important confounders and effect modifiers in this study. The MDV database also does not cover hospital-to-hospital linkages because it is a hospital-based database. Thus, events outside the hospital were not captured. In addition, considering the observation that the median TTNTD is eight months in the first-line cohort, a minimum follow-up period of 180 days might not be optimal for some patients to capture the treatment patterns of the second-line or later therapies. AEs that occurred after discontinuation of a regimen were not collected as they were not in the scope of this study. Medical costs associated with each treatment sequence have not been analyzed in this study and remains a topic for future exploration. Lastly, the findings of this study may deviate from actual practice because the prescription of the regimen is considered an exposure. However, this is unlikely to be a problem because most patients are treated in hospitals.

This study provided insight into the current patterns of drug treatment for mTNBC in Japan. This suggests that the TTNTD shortens as the therapy progresses. However, the later the line of therapy, the more the cost tends to increase, thus suggesting that the cost–benefit balance worsens with later-line treatment, and there is still a high unmet need for mTNBC treatment.