Purpose: Homologous recombination deficiency (HRD) is related to tumorigenesis. Currently, the possibility of HRD as a prognostic biomarker to immune checkpoint inhibitors is unknown. We aimed to investigate whether HRD has potential as a biomarker for immunotherapy. Methods: The status of homologous recombination deficiency (HRD) was assessed with the next-generation sequencing (NGS) TruSight^™ Oncology 500 assay in 501 patients with advanced solid tumor including gastrointestinal (GI), genitourinary (GU), or rare cancer. Results: among the 501 patients, HRD was observed as follows: 74.7% (347/501) patients; GU cancer (92.0%, 23 of 25), colorectal cancer (CRC) (86.1%, 130 of 151), hepatocellular carcinoma (HCC) (83.3%, 10 of 12), pancreatic cancer (PC) (76.2%, 32 of 42), biliary tract cancer (BTC) (75.0%, 36 of 48), sarcoma (65.0%, 39 of 60), melanoma (52.4%, 11 of 21), other GI cancers (50.0%, 11 of 22), and rare cancer (50.0%, 2 of 4). Sixty-five of the 501 patients had received immune checkpoint inhibitors (ICIs) during the course of the disease. Tumor types of 65 patients treated with ICIs are as follows: melanoma (95.2%, 20 of 21), HCC (33.3%, 4 of 12), rare cancer (25.0%, 1 of 4), GC (12.2%, 14 of 116), BTC (10.4%, 5 of 48), and sarcoma (5.0%, 3 of 60). The most frequently reported mutations were BRCA2 (n = 90), ARID1A (n = 77), ATM (n = 71), BARD1 (n = 67). Patients without HRD exhibited an objective response rate (ORR) of 33.3% (4 of 12), and patients with HRD exhibited an ORR of 34.0% (18 of 53). There was no significant difference in ORR between patients with and without HRD (P = 0.967). Progression-free survival (PFS) was 6.5 months (95% CI 0.000–16.175) in patients without HRD and 4.1 months (95% CI 2.062–6.138) in patients with HRD, revealing no statistical significance (P = 0.441). Conclusion: Herein, we reported the status of HRD using a cancer-panel for various solid tumor patients in routine clinical practice and demonstrated that HRD as a single biomarker was not sufficient to predict efficacy of ICIs in solid tumor patients.

Purpose This phase II study investigated whether durvalumab/tremelimumab with proton therapy improves the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients.Materials and Methods Patients who previously received more than one chemotherapy, including at least one platinum-based regimen, and who had at least two measurable lesions were enrolled. Patients received 1,500 mg durvalumab intravenously combined with 75 mg tremelimumab intravenously every 4 weeks for four cycles followed by 1,500 mg durvalumab every 4 weeks. After one cycle of the durvalumab/tremelimumab treatment, proton therapy was given with a total dose of 25 Gy in 5 Gy daily fractions to one of the measurable lesions. We also assessed the ORR in the target lesion outside the radiation field to evaluate the abscopal effect.Results Thirty-one patients were enrolled between March 2018 and July 2020. With 8.6 months of follow-up, the ORR was 22.6% (7/31), including one complete response and six partial responses. The median OS was 8.4 months (95% confidence interval [CI], 2.5 to 14.3) and the median PFS was 2.4 months (95% CI, 0.6 to 4.2). Among the 23 evaluable patients who completed proton therapy, the ORR was 30.4% (7/23). The median OS was 11.1 months (95% CI, 6.5 to 15.8), and the median PFS was 3.7 months (95% CI, 1.6 to 5.7). Grade 3 or higher adverse events were observed in six patients (19.4%) as follows: anemia (n=1), constipation (n=1), electrolyte imbalances (n=2), hyperglycemia (n=1), and pneumonia (n=1).Conclusion The combination of durvalumab/tremelimuab with proton therapy was tolerated well and had encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients.

Purpose: Triple-negative breast cancer (TNBC) is well known for its aggressive course and poor prognosis. In this study, we sought to investigate clinical, demographic, and pathologic characteristics and treatment outcomes of patients with refractory, metastatic TNBC selected by a clinical data warehouse (CDW) approach. Patients and methods: Data were extracted from the real-time breast cancer registry integrated into the Data Analytics and Research Window for Integrated Knowledge C (DARWIN-C), the CDW of Samsung Medical Center. Between January 1997 and December 2019, a TNBC cohort was searched for in the breast cancer registry, which includes records from more than 40,000 patients. Among them, cases of pathologically confirmed metastatic TNBC (mTNBC) were selected as the cohort group (n = 451). The extracted data from the registry via the CDW platform included clinical, pathological, laboratory, and chemotherapy information. Refractory TNBC was defined as confirmed distant metastasis within one year after adjuvant treatment. Results: This study comprised a total of 451 patients with mTNBC, including 69 patients with de novo mTNBC, 131 patients in the nonrefractory TNBC group with confirmed stage IV disease after one year of adjuvant treatment, and 251 patients with refractory mTNBC, whose disease recurred as stage IV within one year after completing adjuvant treatment. The refractory mTNBC cohort was composed of patients with disease that recurred at stage IV after surgery (refractory mTNBC after surgery) (n = 207) and patients in whom metastasis was confirmed during neoadjuvant chemotherapy (unresectable TNBC due to progression during neoadjuvant chemotherapy) (n = 44). Patients in the refractory mTNBC group were younger than those in the nonrefractory group (median age 46 vs. 51 years; p < 0.001). Considering the pathological findings, the refractory group had a greater proportion of cases with Ki-67 ≥ 3+ than did the nonrefractory group (71% vs. 47%; p = 0.004). During a median 8.4 years of follow-up, the overall survival was 24.8 months in the nonrefractory mTNBC group and 14.3 months in the refractory mTNBC group (p < 0.001), and the median progression-free survival periods were 6.2 months and 4.2 months, respectively (p < 0.001). The median disease-free survival period was 30.1 months in the nonrefractory mTNBC group and only 7.6 months in the refractory mTNBC group. Factors related to metastatic sites affecting overall survival were liver metastasis at diagnosis (p < 0.001) and leptomeningeal involvement (p = 0.001). Conclusions: We revealed that patients with refractory mTNBC had a much poorer prognosis among all mTNBC cases and described the characteristics of this patient group.

Sung HH, et al. Investig Clin Urol. 2022 Mar;63(2):168-174. https://doi.org/10.4111/icu.20210407