Hereditary breast and ovarian cancer syndrome (HBOC) is caused by pathogenic germline variants in BRCA1 or BRCA2 and significantly elevates the risk of breast and ovarian cancers. Emerging evidence suggests that there is also a modestly increased risk of uterine cancers, especially uterine papillary serous carcinoma (UPSC) (1–3). A 2021 meta-analysis reported a 2.2-fold greater risk of uterine cancer, particularly UPSC, in BRCA1/2 mutation carriers [standardized incidence ratio (SIR) 17.97 for UPSC] (4). However, most endometrial carcinomas in carriers are histologically heterogeneous, so the precise relationship between the mutation and uterine carcinosarcoma (UCS) is hard to quantify (3). In addition, a recent genomic study has suggested that UCS shares molecular characteristics with high-grade endometrial carcinomas, highlighting the importance of molecular profiling in understanding tumor biology and guiding therapeutic strategies (5).

UCS is a rare, aggressive neoplasm comprised epithelial and mesenchymal components. It accounts for fewer than 5% of uterine cancers (6). It is typically seen in postmenopausal women, and its incidence peaks in patients over 60. It is exceptionally uncommon in young adults (6). Furthermore, the molecular features and clinical behavior of UCS arising in patients with hereditary cancer syndromes remain poorly characterized.

This report presents a 21-year-old female patient with a BRCA1 mutation who developed UCS. To the best of our knowledge, this represents one of the youngest reported cases of uterine carcinosarcoma associated with hereditary breast and ovarian cancer syndrome. This case suggests a potential need to expand the HBOC tumor spectrum to include early UCS, as well as possible reconsideration of surveillance and risk-reduction strategies in young BRCA mutation carriers.

A 21-year-old woman presented with continuous uterine bleeding. When ultrasound revealed a tumor in the uterine cavity, she was referred to our institution for further evaluation. Relevant family history included a paternal grandmother who had suffered breast and peritoneal cancer, and prostate cancer in a maternal grandfather and a maternal uncle. The patient's laboratory results identified severely low hemoglobin levels (5.5 g/dl). Her hormone levels, including estradiol, luteinizing hormone, follicle-stimulating hormone, and prolactin, were within normal limits. Her levels of lactate dehydrogenase (330 U/l) and cancer antigen (CA) 19-9 (81.6 U/ml) were mildly elevated. Other tumor markers, including CA125 and carcinoembryonic antigen, were within normal limits.

Pelvic magnetic resonance imaging revealed an irregular mass with mild contrast enhancement and restricted diffusion. This protruded from the myometrium into the uterine cavity (Fig. 1A-E). As both cervical and endometrial cytology were negative, a hysteroscopic biopsy of the tumor was performed. The tumor was white, irregular, and showed neovascularization (Fig. 2A). Endometrial biopsy revealed densely proliferating epithelioid cells with nuclear atypia and prominent mitoses, consistent with poorly differentiated carcinoma. However, atypical polygonal cells were also present. Immunohistochemistry showed reduced epithelial marker expression and weak positivity for smooth muscle markers, raising the possibility of carcinosarcoma (Fig. 2B-E). Computed tomography (CT) revealed para-aortic and pelvic lymph node metastasis and multiple pulmonary metastases (Fig. 3A-C). The patient underwent total hysterectomy with bilateral salpingo-oophorectomy to control genital bleeding and obtain a definitive diagnosis.

Histopathological examination revealed a mixture of poorly differentiated endometrioid carcinoma and heterologous sarcomatous components with chondrosarcomatous and rhabdomyosarcomatous differentiation (Fig. 4A-F). This led to a diagnosis of UCS at FIGO stage IVB. The patient underwent comprehensive genomic profiling with FoundationOne^® CDx (Foundation Medicine, Cambridge, MA, USA), a hybrid-capture next-generation sequencing (NGS) assay that interrogate 324 cancer-related genes, including POLE, and selected introns to detect base substitutions, insertions/deletions, copy-number alterations, and gene rearrangements. The report also included tumor mutational burden (TMB), microsatellite (MS) status, and homologous recombination deficiency (HRD) signature. Results showed a BRCA1 V923fs*76 mutation [variant allele frequency (VAF): 81.5%], a TP53 splice-site mutation (920-2A>G; VAF: 62.8%), and a PIK3CA Q546K mutation (VAF: 10.2%). The tumor was HRD signature-positive, MS-stable, and had a TMB of 2 mutations per megabase (2 Muts/Mb). Germline genetic testing for BRCA1 and TP53 was performed after genetic counseling, and a germline mutation was identified in BRCA1.

The patient was treated with four cycles of paclitaxel and carboplatin chemotherapy. Subsequently, durvalumab and olaparib were approved for reimbursement under the Japanese national health insurance system for the treatments of endometrial cancer. Therefore, the patient received an additional four cycles of combination chemotherapy with paclitaxel, carboplatin, and durvalumab. Post-chemotherapy CT showed a complete response according to RECIST criteria (Fig. 5A-C). Immunohistochemistry confirmed mismatch repair, and maintenance therapy with durvalumab and olaparib was initiated. The patient has remained progression-free for 10 months.

Carcinosarcoma is unusual in young women, with only sporadic cases reported (7–9), and its occurrence within the HBOC spectrum is exceptionally rare and poorly defined. Prior young-onset reports have lacked broad molecular interrogation: Al Dallal et al (7) assessed p53 and mismatch-repair proteins by immunohistochemistry without comprehensive genomic testing, whereas Soror et al (8) applied a 34-gene NGS panel that included BRCA1/2 and found no pathogenic BRCA1/2 variants. Given the very limited number of young-onset cases reported in the literature, it remains difficult to discuss whether or not differences between races and ethnicities may play a role in disease presentation in this age group. In this regard, our 21-year-old patient underwent comprehensive gene testing that identified a germline BRCA1 frameshift mutation and HRD positivity, establishing HBOC and enabling prediction of sensitivity to platinum chemotherapy and PARP inhibition. This case therefore supports heightened clinical vigilance and a low threshold for early germline evaluation and tumor profiling-particularly in young patients with suggestive personal or family histories-and provides the rationale for the genomically guided treatment strategy described below.

Advances in molecular profiling over the last decade have transformed our understanding of UCS. Integrated genomic analyses, most notably through The Cancer Genome Atlas (TCGA), have characterized UCS as a metaplastic carcinoma arising from a single epithelial clone, with sarcomatous components emerging through epithelial-mesenchymal transition (5). TP53 mutations have been found in around 90% of UCS cases. As in endometrioid and serous uterine carcinomas, alterations are also often seen in PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS (5). TCGA and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) have identified four novel molecular endometrial cancer subgroups (10,11). These are POLE/ultramutated (POLE), microsatellite-instable/hypermutated (MSI), copy-number-high/TP53-mutant (CNH), and copy-number-low/TP53-wild-type (CNL). A recent meta-analysis of four studies reported the pooled prevalence of the TCGA groups among patients with UCS. These were 5.3% POLE, 7.3% MSI, 73.9% CNH, and 13.5% CNL (12). Travaglino et al (13) performed a systematic review and meta-analysis including 263 uterine carcinosarcoma (UCS) classified according TCGA groups. They found that POLE-mutated tumors had an excellent prognosis with no recurrences or deaths, MSI tumors showed intermediate outcomes, while TP53-mutated tumors (CNH group) and no specific molecular profile (NSMP) tumors (CNL group) were associated with poor survival, paralleling the prognostic pattern observed in endometrioid and serous endometrial carcinoma (13). Clinically, poorer outcomes in TP53-abnormal endometrial cancer likely reflect enrichment for advanced stage at presentation (14,15) and relative insensitivity to limited adjuvant radiotherapy (15); in addition, p53 overexpression has been linked to radioresistance and inferior survival (15,16). Complementing these observations, a large real-world series (n=2,235) showed tiered survival by molecular class: TP53-mutated UCS had a shorter median overall survival than TP53-mutated endometrioid cancer [27.9 vs. 35.3 months; hazard ratio (HR), 1.3; 95% confidence interval (CI), 1.1–1.5], and even TP53-wild-type UCS underperformed TP53-wild-type endometrioid disease (29.4 vs. 70.7 months; HR, 2.0; 95% CI, 1.5–2.7) (17). Together, these data indicate that while TP53 alterations define the poorest-prognosis subgroup, ‘being UCS’ adds risk beyond TP53 class alone.

Our patient's tumor harbored a TP53 splice-site mutation and a PIK3CA Q546K mutation, consistent with the molecular hallmarks of UCS that have been identified in large cohorts. To the best of our knowledge, no studies have yet investigated the functional implications of TP53 splice-site mutations and PIK3CA Q546K mutations in UCS. Furthermore, the absence of POLE mutations and a microsatellite-stable status led to its classification as the CNH subtype. Importantly, our patient also carried a germline BRCA1 mutation, and the high variant allele frequency of 81% strongly suggests biallelic inactivation within the tumor, highlighting a potential driver event in tumorigenesis. This finding is particularly notable because, in a cohort of 167 UCS, Sia et al (18) reported germline mutations in 19 patients (11%); however, all affected individuals were aged 52–81 years (median, 61), and individual-level data were not available. In contrast, our patient was diagnosed at the exceptionally young age of 21, making this case one of the earliest-onset UCS associated with a germline BRCA1 mutation reported to date. In the Sia cohort, six out of 167 cases (3.6%) harbored germline BRCA1/2 mutations, and the corresponding tumors exhibited biallelic inactivation, indicating these alterations are likely oncogenic drivers in UCS (18). Consistently, in a series of endometrial cancers with germline BRCA mutations, UCS comprised 28.5% of cases (6/21), further supporting a link between BRCA-associated tumorigenesis and this aggressive histologic subtype (19). Nevertheless, a lack of IHC is a limitation of the present study.

Based on the results of the GOG-232B and GOG-261 trials, the recommended first-line treatment for advanced UCS is a carboplatin/ paclitaxel doublet due to its non-inferiority and good toxicity profile (20,21). However, the outcomes previously reported in stage IV cases have been poor, with a median overall survival time of just 8 months (22). Notably, tumors exhibiting HRD, particularly those with BRCA mutations, have increased sensitivity to platinum chemotherapy due to their impaired DNA repair capabilities. Thus, our patient's complete radiologic response following four cycles of paclitaxel/carboplatin may be attributable to an underlying HRD-driven susceptibility (23). This suggests the potential utility of HRD and BRCA testing of patients with UCS to predict chemosensitivity.

Recent preclinical studies have elucidated the mechanisms behind the synergistic effects of combined PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICIs), and support the superiority of this approach over PARPi monotherapy. PARP inhibition induces DNA double-strand breaks. The accumulation of these breaks causes the activation of cyclic GMP-AMP synthase (cGAS). This is a stimulator of interferon genes (STING) pathway that enhances type I interferon signaling and dendritic cell recruitment, promoting antitumor immunity (24). PARP inhibition also upregulates PD-L1 expression via the inactivation of GSK3β, contributing to immune evasion and creating a therapeutic window for ICIs (25). These immunomodulatory effects are further amplified in HRD tumor models, where the combination of PARPi and anti-PD-1/PD-L1 antibodies provides superior cytotoxic T-cell infiltration and tumor regression compared to monotherapy (26). Collectively, these findings provide a strong biological rationale for combined PARPi-ICI therapy in HRD tumors. Combination ICIs and PARPi are garnering increased attention in gynecological oncology. The phase III DUOE trial included patients with advanced or recurrent endometrial cancer, including UCS. The trial found that adding durvalumab to carboplatin and paclitaxel treatment, and following with maintenance durvalumab and olaparib, significantly improved progression-free survival (PFS). Specifically, the PFS hazard ratios (HRs) were 0.71 (durvalumab arm) and 0.55 (durvalumab and olaparib arm) versus chemotherapy alone (27). In a subgroup analysis of tumors harboring homologous recombination repair mutations, the PFS HR was 0.30 in the durvalumab and olaparib arm compared to chemotherapy alone (27). This provides compelling grounds for applying this combination strategy to HRD-positive UCS.

Compared with our case, Wan et al (28) reported a 58-year-old postmenopausal UCS with bilateral benign ovarian Brenner tumors showing diffuse mutant-type p53 on IHC; the report focuses on pathology and does not include TCGA/ProMisE molecular stratification, HRD status, germline testing, or systemic-therapy outcomes. By contrast, our case demonstrates the successful application of targeted and immunological therapy guided by precise molecular characterization in a young patient with UCS. Comprehensive genomic profiling (TP53 mutation, PIK3CA alteration, BRCA1 frameshift, and HRD positivity) informed a personalized treatment plan combining platinum-based chemotherapy, immune checkpoint blockade, and PARP inhibition. This resulted in complete and durable remission. Our findings support the use of routine genomic profiling, including HRD testing, in UCS. Clinical trials targeting HRD-positive, MMR-proficient UCS are needed to further investigate treatment strategies such as that described herein. Such strategies may transform the prognosis for this aggressive and historically intractable cancer subtype.