The VEGF-Hypoxia Signature is Upregulated in Basal like Breast Tumors from Women of African Ancestry and Associated with Poor Outcomes in Breast Cancer.

PURPOSE: Black women experience the highest breast cancer mortality rate compared to women of other racial/ethnic groups. To gain a deeper understanding of breast cancer heterogeneity across diverse populations, we examined a VEGF-hypoxia gene expression signature in breast tumors from women of diverse ancestry. EXPERIMENTAL DESIGN: We developed a NanoString nCounter gene expression panel and applied it to breast tumors from Nigeria (n=182) and the University of Chicago (n=161). We also analyzed RNA sequencing data from Nigeria (n=84) and TCGA datasets (n=863). Patient prognosis was analyzed using multiple datasets. RESULTS: The VEGF-hypoxia signature was highest in the basal-like subtype compared to other subtypes, with greater expression in Black women compared to White women. In the TCGA dataset, necrotic breast tumors had higher scores for the VEGF-hypoxia signature compared to non-necrosis tumors (p<0.001), with the highest proportion in the basal-like subtype. Furthermore, necrotic breast tumors have higher scores for the proliferation signature, suggesting an interaction between the VEGF-hypoxia signature, proliferation and necrosis. T cell gene expression signatures also correlated with the VEGF-hypoxia signature when testing all tumors in the TCGA dataset. Lastly, we found a significant association of the VEGF-hypoxia profile with poor outcomes when using all patients in the METABRIC (p<0.0001) and SCAN-B datasets (p=0.002). CONCLUSIONS: These data provide further evidence for breast cancer heterogeneity across diverse populations and molecular subtypes. Interventions selectively targeting VEGF-hypoxia and the immune microenvironment have the potential to improve overall survival in aggressive breast cancers that disproportionately impact Black women in the African Diaspora.

Identification of germline population variants misclassified as cancer-associated somatic variants.

Introduction: Databases used for clinical interpretation in oncology rely on genetic data derived primarily from patients of European ancestry, leading to biases in cancer genetics research and clinical practice. One practical issue that arises in this context is the potential misclassification of multi-ancestral population variants as tumor-associated because they are not represented in reference genomes against which tumor sequencing data is aligned. Methods: To systematically find misclassified variants, we compared somatic variants in census genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) V99 with multi-ancestral population variants from the Genome Aggregation Databases' Linkage Disequilibrium (GnomAD). By comparing genomic coordinates, reference, and alternate alleles, we could identify misclassified variants in genes associated with cancer. Results: We found 192 of 208 genes in COSMIC's cancer-associated census genes (92.31%) to be associated with variant misclassifications. Among the 1,906,732 variants in COSMIC, 6,957 variants (0.36%) aligned with normal population variants in GnomAD, concerning for misclassification. The African / African American ancestral population included the greatest number of misclassified variants and also had the greatest number of unique misclassified variants. Conclusion: The direct, systematic comparison of variants from COSMIC for co-occurrence in GnomAD supports a more accurate interpretation of tumor sequencing data and reduces bias related to genomic ancestry.

Outcome differences by sex in oncology clinical trials.

Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. Among 288 trials with comparisons of survival, outcome, or response, 16% report males having statistically significant better survival outcome or response, while 42% reported significantly better survival outcome or response for females. The strongest differences are in trials of EGFR inhibitors in lung cancer and rituximab in non-Hodgkin's lymphoma (both favoring females). Among 44 trials with side effect comparisons, more trials report significantly lesser side effects in males (N = 22) than in females (N = 13). Thus, while statistical comparisons between sexes in oncology trials are rarely reported, important differences in outcome and toxicity exist. These considerable outcome and toxicity differences highlight the need for reporting sex differences more thoroughly going forward.

Characterization of Oncology Clinical Trials Using Germline Genetic Data.

Importance: The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy. Objective: To characterize past and ongoing oncology trials that use germline data. Design, Setting, and Participants: This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included. Main Outcomes and Measures: Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined. Results: A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic biomarkers. PARP inhibitors or immunotherapy were tested in 69.9% of trials; PARP inhibition was the most frequently studied mechanism (367 trials [41.4%]). An overwhelming number of trials using germline data were conducted in the US, Canada, and Europe vs other countries, mirroring disparities in cancer genetics data. Germline data in inclusion and exclusion criteria are associated with altered end point, outcomes, and enrollment compared with oncology trials with no germline data use. Examples of inclusion and exclusion criteria regarding germline data that may unintentionally exclude patients were identified. Conclusions and Relevance: These findings suggest that for germline biomarkers to gain clinical relevance, trials must expand biomarkers, therapies, and populations under study.

Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).

PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants.

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.

Telomere biology disorder prevalence and phenotypes in adults with familial hematologic and/or pulmonary presentations.

Telomere biology disorders (TBDs) present heterogeneously, ranging from infantile bone marrow failure associated with very short telomeres to adult-onset interstitial lung disease (ILD) with normal telomere length. Yield of genetic testing and phenotypic spectra for TBDs caused by the expanding list of telomere genes in adults remain understudied. Thus, we screened adults aged ≥18 years with a personal and/or family history clustering hematologic disorders and/or ILD enrolled on The University of Chicago Inherited Hematologic Disorders Registry for causative variants in 13 TBD genes. Sixteen (10%) of 153 probands carried causative variants distributed among TERT (n = 6), TERC (n = 4), PARN (n = 5), or RTEL1 (n = 1), of which 19% were copy number variants. The highest yield (9 of 22 [41%]) was in families with mixed hematologic and ILD presentations, suggesting that ILD in hematology populations and hematologic abnormalities in ILD populations warrant TBD genetic testing. Four (3%) of 117 familial hematologic disorder families without ILD carried TBD variants, making TBD second to only DDX41 in frequency for genetic diagnoses in this population. Phenotypes of 17 carriers with heterozygous PARN variants included 4 (24%) with hematologic abnormalities, 67% with lymphocyte telomere lengths measured by flow cytometry and fluorescence in situ hybridization at or above the 10th percentile, and a high penetrance for ILD. Alternative etiologies for cytopenias and/or ILD such as autoimmune features were noted in multiple TBD families, emphasizing the need to maintain clinical suspicion for a TBD despite the presence of alternative explanations.

Black Lives Matter Worldwide: Retooling Precision Oncology for True Equity of Cancer Care.

In a recent issue of Cancer Cell, Carrot-Zhang et al. identified ancestry-specific molecular variants and expression changes among patients from The Cancer Genome Atlas (TCGA).1 Their study findings and limitations highlight the critical need to diversify populations represented in cancer genomics research.

Employment trends in young women following a breast cancer diagnosis.

PURPOSE: Little is known about how a breast cancer diagnosis and treatment affects job-related outcomes in young women with breast cancer, who are an integral part of the workforce. We sought to describe employment trends among young breast cancer survivors. METHODS: 911 women with non-metastatic breast cancer were surveyed about employment-related outcomes 1 year post-diagnosis. Participants were enrolled in the Young Women's Breast Cancer Study an ongoing, multi-center cohort of women diagnosed with breast cancer at age ≤ 40. RESULTS: Among 911 women, median age at diagnosis was 36 years (range 17-40). Most women (80%, n = 729) were employed 1 year post-diagnosis. Among the 7% (n = 62) employed before diagnosis but who reported unemployment at 1 year, approximately half reported they were unemployed for health reasons. Among employed women, 7% said treatment affected their ability to perform their job. Women with stage-three disease (vs. stage 1 disease, odds ratio (OR): 3.73, 95% CI 1.39-9.97) and those who reported having money to pay bills after cutting back or difficulty paying bills at baseline (vs. having enough money for special things, OR 2.70, 95% CI 1.32-5.52) at baseline were more likely to have transitioned out of the workforce. CONCLUSIONS: Our results suggest an impact of disease burden and socioeconomic status on employment in young breast cancer survivors. There is a need to ensure young survivors who leave the workforce following diagnosis are sufficiently supported given the potential adverse psychosocial and financial impacts of unemployment on survivors, their families, communities, and society.

Chemotherapy for advanced cancers.

The decision to treat with chemotherapy in advanced cancers is a complex process that requires oncologists to weigh the indications and benefits. Treatment of patients with advanced cancer is typically multidimensional and should ideally include oncologists in coordination with palliative care specialists. When the intent of chemotherapy for patients with advanced neoplasms is no longer curative, palliative care can and should be delivered simultaneously with antineoplastic agents. Often, chemotherapy for advanced cancers is delivered in an attempt to palliate symptoms, and therefore improve quality of life (QOL). The role of palliative chemotherapy should be continually reevaluated throughout the trajectory of the patient's illness. When chemotherapy is no longer controlling the disease or helping symptoms, the role of chemotherapy should be reconsidered. This review aims to provide a foundation for discussions about treatment of patients with advanced malignancies.