In this study, a panel test of 160 cancer-related genes was conducted, which revealed that both actionable and druggable gene alterations were found in 95% of the cases (19/20). The most frequent actionable gene mutation was TP53 (35%), followed by PTEN (20%), and PIK3CA (20%). It has been reported that PIK3CA is more frequently found in solid tumors, such as breast cancer and lung cancer [7]. In gynecological cancers, it has also been reported that gene alterations of PTEN and PIK3CA are more frequent [8]. PTEN mutations were found in 50% of endometrial cancer [9]. In other reports of endometrial cancer, PIK3CA was detected in 22% of cases [10] and Makker et al. [11] reported it to be in 24% of cases. The results for the detected gene alterations in this study were similar to those reported previously.
In addition, in this study, we compared the differences in gene mutations between the primary and metastatic lesions in two cases. However, almost similar distributions of genetic alterations were observed in either case, and the actionable mutations were similar. The current finding is similar to those in previous reports, which state that there is almost no difference in actionable mutations between the primary and metastatic lesions [7].
In this study, druggable gene alterations were found in 95% of the cases. The SHIVA trial reported that gene alteration that could lead to treatment was found in 40% of cases [12] and another study [13] reported that clinically actionable genes were detected in 37% of cases, while the MOSCATO 01 trial reported it to be in 49.3% of cases [14]. Compared with previous reports, more druggable gene alterations were detected in the current study.
However, in reality, only 35% of the patients (7/20) received genotype-matched therapy. A study so far conducted in Japan reported that targeted therapy was performed in 13.3% [15], and another study [16] reported that it was performed in 15.2% of the patients. Thus, the patients who were able to receive targeted therapy were limited. The main reasons for failure included worsening condition before treatment and lack of participation in clinical trials. In addition, the availability of off-label drugs depended on the patient's financial status. All of these issues have been highlighted in similar reports [17, 18]; therefore, it is important to conduct genomic tests earlier and determine the available drugs or clinical trials before the patient's condition deteriorates.
Of the seven patients who received genotype-matched therapy, five had endometrial cancer, one had cervical cancer, and one had ovarian cancer. Of these patients, only three patients with endometrial cancer (43%) achieved the effectiveness of genotype-matched therapy. These three successful patients remained without any deterioration in patient condition for more than half a year; however, all cases recurred within 9–13 months after the initiation of genotype-matched therapy. Some previous trials have evaluated the effectiveness of genotype-matched therapy in patients with difficult-to-treat cancers. The MOSCATO 01 trial [14] showed improved outcomes in 33% of patients with advanced cancers. In the SAFIR01 trial [19], 30% of the patients had an objective response or SD. In the SHIVA randomized trial [12] when comparing genotype-matched therapy and conventional standard therapy, no significant difference was found in progression-free survival. In contrast, according to another report, genotype-matched therapy had a better outcome than unmatched therapy [20].
Patients who received targeted therapy had better outcomes than those who did not. One patient with PTEN mutation received the mTOR inhibitor i.e. everolimus treatment, the second patient with TSC2 mutation also received everolimus and an aromatase inhibitor, letrozole. PTEN and TSC2 genes are related to the phosphoinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. This pathway is often dysregulated in gynecological cancers [21] and is associated with an aggressive disease and a poor prognosis [22]. Therefore, mTOR inhibitors may provide a novel therapeutic approach for the dysregulation of the PI3K/AKT/mTOR pathway. The effectiveness of a single-agent therapy with mTOR inhibitors in recurrent metastatic EC has been reported [10]. Furthermore, recently, letrozole in combination with everolimus showed a high clinical benefit rate and response rate in a phase II clinical trial in advanced EC [23]. In this study, mTOR inhibitors were effective in both patients, therefore, we expect that mTOR inhibitors could improve prognosis in recurrent EC with dysregulation of the PI3K/AKT/mTOR pathway. However, in advanced gynecological cancers, which exhibits standard treatment resistance, the effect of PI3K pathway inhibitors is not due to mutations in the PI3K pathway [8]. Further investigation of the effect of mTOR inhibitors is warranted.
In this study, we showed that genomic testing will be useful in advanced recurrent gynecological cancer to identify new treatment options based on gene alterations. The limitation of this study is the small sample size. To overcome this limitation, strategies are being devised to increase the number of patients for clinical sequencing in our hospital. Furthermore, genotype-matched therapy may help improve gynecological cancer outcomes. Recently, cancer genomic tests have become available for the health insurance system in Japan, and whole exome analysis has also been investigated at one's own expense. Therefore, more genomic alterations are expected to be revealed for larger sample sizes.