JCO precision oncology最新文献

Purpose: Multifactorial breast cancer (BC) risk prediction models use a range of predictors to estimate an individual's chance of developing BC. Data on risk factors are often incomplete, and point estimates calculated when data are missing can mask considerable uncertainty. Quantifying this uncertainty is critical for effective risk communication.

Methods: We used Monte Carlo simulation methods to estimate the distribution of 10-year BC risk for individuals with missing data, using the BOADICEA multifactorial model as an example. Multivariate imputation by chained equations with large representative reference data sets was used to sample missing covariates. We developed a framework for estimating the uncertainty distribution, uncertainty intervals (UIs), and probability of reclassification, which can be applied to any given individual with missing risk factor data. This was applied to estimating individual-level uncertainty distributions and quantifying the probability of reclassification when groups of risk factors are measured, for a range of example women.

Results: Women with limited risk factor data had considerable uncertainty in their estimated BC risk, and 95% UIs spanned all risk categories. This was especially relevant for women classified as moderate-risk, such as those with strong family history or a moderate-risk pathogenic variant. Reclassification probability in this case was as high as 57.5%, with 95% UI of 0.9% to 9.3% for the 10-year risk from age 40 years. Risk certainty improved with additional data collection, particularly genetic information or mammographic density measurement.

Conclusion: Our results demonstrate that, in some cases, there is considerable probability of reclassification after collecting missing data. Methodology presented here can identify situations where it would be most beneficial to collect additional information, to enable better informed clinical decision making.

Purpose: Up to 1% of patients with non-small cell lung cancer harbor germline epidermal growth factor receptor (EGFR) mutations, although they remain poorly described in unselected, noncancer populations. We sought to characterize the prevalence of germline EGFR mutations in Southeastern United States.

Methods: We assessed the prevalence of EGFR mutations in unselected cohorts of individuals enrolled in the Duke CATHeterization GENetics, gnomAD, UK Biobank, and All of Us studies. We additionally performed comprehensive chart review for patients evaluated at the Duke Cancer Institute with germline EGFR mutations.

Results: We found the prevalence of germline EGFR T790M to be >1 in 3,000 individuals in the Duke catchment area. This prevalence was 7.5 times greater than the national All of Us cohort, 3.7 times greater than the international gnomAD cohort, and 55.8 times greater than the UK Biobank cohort. The Southeastern region also contained the highest proportion of T790M carriers in the All of Us cohort. Twenty-eight individuals with suspected germline EGFR mutations were identified in our institutional cohort. The majority of these patients did not have a history of smoking, had multiple lung nodules at the time of diagnosis, and had a family history of cancer. Forty-five percent of patients had a diagnosis of a second primary malignancy.

Conclusion: Our analysis represents the largest study to date assessing the prevalence of germline EGFR mutations from both patients with lung cancer and unselected cohorts of individuals and presents evidence for increased prevalence of EGFR T790M mutations within the Southeastern United States. Given the high prevalence and documented hereditary risk of germline EGFR mutations, future studies investigating the role of familial testing and screening in these individuals is warranted.

Purpose: Anal adenocarcinoma (AD) is a rare GI malignancy with no established standard treatment. Little is known about genomic alterations (GAs) and their therapeutic implications in advanced anal AD. Here, we compared the genomic profiles of advanced anal AD and advanced rectal AD.

Methods: We retrospectively extracted data from patients with advanced anal or rectal AD who underwent comprehensive genomic profiling (CGP) and were registered at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB).

Results: From June 2019 to April 2023, 45 patients with anal AD and 1,915 patients with rectal AD were enrolled into the C-CAT database. TP53 (88.9%) and KRAS (51.1%) were the most common GAs in anal AD. Compared with rectal AD, anal AD showed significantly higher frequencies of ERBB3 (22.2% v 1.8%), MYC (20.0% v 8.4%), and BRCA2 (6.7% v 1.5%) alterations and a significantly lower frequency of APC mutations (8.9% v 84.6%). TMB-high status (≥10 mutations/Mb) was observed in 6.7% of anal AD cases, whereas no MSI-high tumors were identified in this group. At least one druggable GA (excluding RAS, BRAF V600E, ERBB2, and MSI) was detected in 40.0% of patients with anal AD. Druggable GAs were identified in genes related to the MAPK pathway, DNA damage response pathway, and other oncogenic pathways.

Conclusion: Advanced anal AD exhibited a distinct genomic profile compared with advanced rectal AD. CGP is a useful approach for identifying druggable GAs in advanced anal AD to expand therapeutic opportunities.

Purpose: Homologous recombination deficiency (HRD) results in DNA instability in tumor cells and contributes to tumor pathogenesis. Although HRD-directed therapies are established in other cancers, their role in skin cancers remains unclear. Given the poor response to standard therapies in skin cancer subtypes like acral and mucosal melanoma, we aimed to characterize the prevalence of HRD across skin cancer subtypes, evaluate its correlation with immune checkpoint inhibitor (ICI) response biomarkers, and assess its prognostic relevance in patients treated with immunotherapy (IO).

Methods: A total of 2,508 patients with skin cancer underwent molecular profiling including whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry. HRD status was defined by a high loss of heterozygosity (LOH-high) or mutations in homologous recombination repair (HRR) genes. Associations between HRD and established ICI biomarkers (tumor mutational burden, PD-L1, deficient mismatch repair/microsatellite instability-high, immune cell fractions, and transcriptomic signatures) were assessed. Survival outcomes on ICI therapy were assessed in cutaneous melanoma using insurance claims data.

Results: Overall, among the melanoma subtypes, mucosal and acral melanoma had a greater prevalence of LOH-high than cutaneous (30.9% v 13.1% v 8.3%, P < .001). Generally, LOH-high in skin cancer did not correlate with mutations in HRR genes. Additionally, there was no significant association in ICI response biomarkers and HRD among patients with skin cancers. Furthermore, HRD was not associated with a prognostic advantage following IO (hazard ratio, 0.981 [CI, 0.80 to 1.20]; P = .854).

Conclusion: HRD defines a biologically distinct subset of skin cancers and is not predictive of ICI response or improved outcomes. The high prevalence of HRD in acral and mucosal melanoma highlights the need to investigate HRD-directed therapies strategies in this distinct cohort, such as poly (ADP-ribose) polymerase inhibitors or platinum-based therapies.

Purpose: The tumor-agnostic approach has been increasingly adopted in precision oncology. Immunohistochemistry (IHC) is the standard biomarker testing for human epidermal growth factor receptor 2 (HER2)-targeted therapies, whereas next-generation sequencing (NGS) has been widely incorporated in routine clinical practices. Here, we investigated the concordance between NGS-based assays and IHC in HER2 testing. Interfering factors leading to discordant results between the assays were also studied.

Materials and methods: Over 78,000 solid tumors across various types from two independent cohorts in the United States and Japan were investigated for HER2 DNA copy number, mRNA expression, and protein overexpression by whole-exome sequencing (WES), whole-transcriptome sequencing (WTS), and IHC, respectively.

Results: In the US cohort (n = 77,267), HER2 DNA amplification, mRNA overexpression, and IHC-positive (IHC-P) were detected in 4.9%, 10.1%, and 4.7% of the tumors, respectively. Positive results in at least one of the three assays were observed in 10.7% of tumors, while 3.9% were positive for all three assays. Using IHC as a comparator, WTS showed better sensitivity than WES but a lower positive predictive value. These results were consistent in the Japanese cohort (n = 1,225). Although the overall HER2 RNA expression level correlated well with IHC score and DNA copy number, the degree of correlation varied among tumor types. Heterogeneous distribution of IHC-P tumor cells was associated with discordant results between NGS-based assays and IHC.

Conclusion: HER2-positive status in protein, mRNA, and DNA showed concordance in general but varied among tumor types. NGS-based assays, especially WTS, could be a useful predictive tool for HER2 testing in tumor-agnostic settings. Intratumor heterogeneity in HER2 protein expression should be considered when bringing bulk sequencing tests into clinical settings.

Purpose: Early-onset endometrial cancer (eoEC) is increasing, and germline drivers may be enriched in younger patients. We sought to define germline pathogenic variants (gPVs) in those with EC by age.

Methods: We identified patients with EC who underwent clinical tumor-normal sequencing from December 2014 to June 2021 and collected clinical variables. Logistic regression models evaluated associations between age at EC diagnosis and presence of gPV, biallelic inactivation, and Lynch Syndrome (LS). Age categories were defined as early-onset (eoEC, EC < 50 years) and late-onset (EC ≥ 70 years) and were compared with those diagnosed ages 50-69 years.

Results: Among 1,625 patients with EC, the median age at diagnosis was 63 (range, 24-96) years. We observed gPV in 28 (16%) of 170 patients with eoEC, 152 (14%) of 1,066 patients diagnosed age 50-69 years, and 36 (9%) of 389 patients with late-onset EC (P = .016). LS was enriched in eoEC, with 6.5% of patients diagnosed age <50 years having LS. In multivariable models compared with those with EC diagnosed age 50-69 years, eoEC was more likely to exhibit biallelic inactivation (odds ratio, 3.34 [95% CI, 1.44 to 7.35]) and be associated with LS (hazard ratio [HR], 3.49 [95% CI, 1.63 to 7.01]). Among early-onset EC, 14 (50%) of 28 gPV were high penetrance and 14 (50%) of 28 exhibited biallelic inactivation. However, heterogeneity was observed, and rates of gPV were 8.9% and 19%, biallelic inactivation was 0% and 11%, and LS was 2.2% and 8% in those diagnosed age <40 years and 40-49 years, respectively.

Conclusion: Rates of gPV, biallelic inactivation, and LS differ across age groups for EC, with high-penetrant genes driving tumorigenesis enriched in younger patients. However, very-early-onset EC may have different drivers and necessitates more research.