Changxia Shao

Background/Objectives: Mutations in BRCA1 and/or BRCA2 (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors. Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy. Results: Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61–1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69–0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68–1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73–1.18) with/without HRRm (n = 132/n = 1488). Conclusions: Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity >= 16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

Introduction: Hypoxia‐inducible factor‐2α (HIF‐2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF‐2α are poorly understood, with limited understanding of the prevalence and clinical prognosis.Methods: This retrospective observational study used a de‐identified nationwide (US‐based) clinico‐genomic database (CGDB) across 15 available tumor types.Results: Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above‐mentioned six genes was observed in 1.8% (95% CI: 1.5–2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF‐2α gene mutations in the study population was 0.9% (95% CI: 0.8–1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF‐2α gene mutation was 14.5 (95% CI: 11.5–24.2) and 9.3 (95% CI: 6.0–18.1) months, respectively, compared with 13.4 (95% CI: 12.9–13.9) and 9.8 (95% CI: 9.3–10.4) months among patients without HIF‐2α gene mutations.Discussion and Conclusions: The prevalence of HIF‐2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF‐2α gene mutation status and OS was identified among patients evaluated in this study.

Introduction Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset. Methods Deidentified data for patients who had undergone comprehensive genomic profiling using FoundationOne^®CDx were collected through December 31, 2020, from a real-world multi-tumor clinico-genomic database (CGDB) capturing data from clinics in the United States. Patients eligible for inclusion in this analysis had a confirmed diagnosis with advanced or metastatic disease between January 1, 2018, and December 31, 2019, for 1 of 15 solid tumor types. Objectives were to evaluate patient treatment patterns by BRCAm, HRRm, and HRD status and to describe the timing of when (throughout disease course) comprehensive genomic profiling was performed. Results Among 9457 patients included in the overall population with evaluable biomarker status, 7856 (83.1%) received ≥ 1 systemic therapy. Among the 7856 patients who received systemic therapy, 2324 (30.0%) underwent testing before first-line therapy, 4114 (52.4%) were tested after receiving first-line therapy and before receiving subsequent therapy (if any), 970 (12.3%) were tested after second-line therapy and before receiving subsequent therapy (if any), and 447 (5.7%) patients underwent testing after receiving third-line therapy. A higher proportion of patients with BRCAm, HRRm, or HRD-positive status were treated with poly(ADP-ribose) polymerase (PARP) inhibitors across all lines of therapy. There was no evidence of a meaningful difference in the proportion of patients who received other treatment (including chemotherapy and immunotherapy) by BRCAm, HRRm, or HRD status. Conclusion The majority of patients from this real-world dataset underwent FoundationOne^®CDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors.

The classification of undifferentiated pleomorphic sarcoma (UPS) has been evolving with advances in immunohistochemistry and genomic profiling over the past 20 years. There is a lack of current information on UPS incidence. Due to the lack of designated histology codes for UPS in the Surveillance, Epidemiology, and End Results (SEERs) program, we estimated UPS incidence by three different definitions based on clinical opinions using the 2000–2020 data from 22 registries of the SEER program. The incidence varied widely across the three definitions with 0.06 per 100,000 persons for the least inclusive definition and 0.67 per 100,000 persons for the most inclusive definition in 2016–2020, making it challenging to estimate the exact incidence of UPS. Regardless, all the incidences decreased between 2000 and 2020. Guidelines in UPS diagnosis and classification need to be better implemented in the US.

Baek MH, et al. J Gynecol Oncol. 2024 May;35:e105. https://doi.org/10.3802/jgo.2024.35.e105

PURPOSE: Mutations in BRCA1 and/or BRCA2 (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy. METHODS: Deidentified data were collected through December 31, 2020, from a real-world clinicogenomic database (CGDB) with data originating from approximately 280 cancer clinics in the United States. Patients age 18 years and older with an advanced/metastatic diagnosis between 2018 and 2019 for 1 of 15 solid tumors and available data in the CGDB were included. The primary analysis evaluated the association between HRR pathway biomarkers and OS, using start of second-line therapy as the index date (to reduce immortal time bias). RESULTS: A total of 9,457 patients had available data for BRCA/HRR and 5,792 for HRD status; 4,890 (51.7%) were women and mean (SD) age was 65.9 (11.5) years. For the primary analysis, adjusted hazard ratios for OS were BRCAm (n = 156) versus BRCA wild-type (wt; n = 3,131; 0.83 [95% CI, 0.60 to 1.17]); for HRRm (n = 467) versus HRRwt (n = 282; 0.95 [95% CI, 0.79 to 1.14]); and for HRD-positive (n = 447) versus -negative (n = 1,687; 1.22 [95% CI, 1.02 to 1.47]). Results were similar using start of first-line and start of third-line therapy as index dates. CONCLUSION: This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.

PURPOSE: Evaluating whether patient populations in clinico-genomic oncology databases are comparable with whom in other databases without genomic component is important. METHODS: Four databases were compared for colorectal cancer (CRC) cases and stage IV CRC cases: American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE-BPC), The Cancer Genome Atlas (TCGA), SEER-Medicare, and MarketScan Commercial and Medicare Supplemental claims databases. These databases were also compared with the SEER registry database which serves as national benchmarks. Demographics, clinical characteristics, and overall survival were compared in patients with newly diagnosed CRC and patients with stage IV CRC across databases. Treatment patterns were further compared in patients with stage IV CRC. RESULTS: A total of 65,976 patients with CRC and 13,985 patients with stage IV CRC were identified. GENIE-BPC had the youngest patient population (mean age [years]: CRC, 54.1; stage IV CRC, 52.7). SEER-Medicare had the oldest patient population (CRC, 77.7; stage IV CRC, 77.3). Most patients were male and of White race across databases. GENIE-BPC had the highest proportion of patients with stage IV CRC (48.4% v other databases 13.8%-25.4%) and patients receiving treatments (95.7% v 37.6%-59.1%). Infusional fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab was the most common regimen across databases accounting for 47.3%-78.5% of patients receiving first line of therapy. The median survival from diagnosis was 36, 94, 44 months (CRC) and 23, 36, 15 months (stage IV CRC) for patients in GENIE-BPC after left truncation, TCGA, and SEER-Medicare databases, respectively. CONCLUSION: Compared with other databases, GENIE-BPC had the youngest patients with CRC with the most advanced disease and the largest proportion of patients receiving treatment. Investigators should consider adjustments when extrapolating results from clinico-genomic databases to the general CRC population.

Patients with BRCA1/2 mutations (BRCAm), loss-of-function mutations in other homologous recombination repair (HRRm) genes, or tumors that are homologous recombination deficiency positivity (HRD+) demonstrate a robust response to PARPi therapy. We conducted a systematic literature review and meta-analysis to evaluate the prognostic value of BRCAm, HRRm, and HRD+ on overall survival (OS) among those treated by chemotherapy or targeted therapy other than PARPi across tumor types. A total of 135 eligible studies were included. Breast cancer (BC) patients with BRCA1/2m had a similar overall survival (OS) to those with wild-type BRCA1/2 (BRCA1/2 wt) across 18 studies. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2 wt across 24 studies reporting BRCA1m and BRCA2m, with an HR of 0.7 (0.60.8). Less OS data were reported for other tumors: 6 studies for BRCA2m compared with BRCA2 wt in prostate cancer with an HR of 1.9 (1.13.2) and 2 studies for BRCA1/2m compared with BRCA1/2 wt in pancreatic cancer with an HR of 1.5 (0.83.1). Only 4 studies reported HRD+ by either BRCA m or genomic instability score (GIS)42 and OS by HRD status. The HR was 0.67 (0.431.02) for OS with HRD+ vs. HRD. A total of 15 studies reported the association between HRRm and OS of cancers in which one or more HRR genes were examined. The HR was 1.0 (0.71.4) comparing patients with HRRm to those with HRR wild-type across tumors. Our findings are useful in improving the precision and efficacy of treatment selection in clinical oncology.