Morbidity and mortality of fragility proximal humerus fractures: a retrospective cohort study of patients presenting to a level one trauma center.

PURPOSE: Fragility fractures are a significant source of morbidity and have high associated mortality. Identifying risk factors for poor outcomes is essential for guiding treatment and for setting expectations for patients and their families. Although fragility hip fractures have been abundantly explored, there is a paucity of information regarding proximal humerus fractures (PHFs). METHODS: We retrospectively review the electronic medical records of 379 patients who presented to a level 1 trauma center with a PHF secondary to a fall. Patient demographics, handedness, comorbidities, treatment, imaging data, follow-up data, and death date (if applicable) were recorded. RESULTS: Our cohort consisted of 279 females and 100 males with an average age of 71.4 years. Distribution of injuries was 178 left, 141 right, and 7 bilateral. Compared with handedness, 179 were ipsilateral, 141 were contralateral, and 59 were unknown. A total of 81.3% of injuries were treated nonoperatively, whereas 18.7% were managed surgically. One-year mortality was 17.4%, and 2-year mortality was 24.0%.Males demonstrated a 2.28 increased risk of 1-year mortality (P = .004). Patients who died within 1 year of fracture had significantly higher Charlson comorbidity index scores (P < .0001) and age (P = .0003). Risk of death was significantly lower in patients who underwent surgery compared with those who were treated nonoperatively (P = .01). Patients who used an assist device before fracture had 4.2 increased risk of 1-year mortality (P < .0001). Patients who presented from nursing homes or assisted living had a 2.1 increased risk of 1-year mortality (P = .02). Patients with severe liver disease had a 5.5 increased risk of 1-year mortality (P < .0001), and those with metastatic cancer had a 13.7 increased risk of 1-year mortality (P < .0001). Bilateral fractures, side of injury in relation to handedness, rehospitalization, Neer classification, and PCP follow-up within 30 days were not associated with increased mortality. CONCLUSIONS: Increased understanding risk factors for mortality after PHF will allow for more informed patient discussions regarding treatment outcomes and risk of death. Our data suggest that mortality at 1 year for fragility PHF is universally high regardless of risk factors. This risk is increased in patients who are older, functionally limited, or who have medical comorbidities. Our data demonstrate the importance of medical optimization of patients with a fragility PHF and underscore the importance of fall prevention in high-risk patients.

Allele-specific epigenetic activity in prostate cancer and normal prostate tissue implicates prostate cancer risk mechanisms.

Genome-wide association studies (GWASs) of prostate cancer have identified >250 significant risk loci, but the causal variants and mechanisms for these loci remain largely unknown. Here, we sought to identify and characterize risk-harboring regulatory elements by integrating epigenomes from primary prostate tumor and normal tissues of 27 individuals across the H3K27ac, H3K4me3, and H3K4me2 histone marks and FOXA1 and HOXB13 transcription factors. We identified 7,371 peaks with significant allele specificity (allele-specific quantitative trait locus [asQTL] peaks). Showcasing their relevance to prostate cancer risk, H3K27ac T-asQTL peaks were the single annotation most enriched for prostate cancer GWAS heritability (40×), significantly higher than corresponding non-asQTL H3K27ac peaks (14×) or coding regions (14×). Surprisingly, fine-mapped GWAS risk variants were most significantly enriched for asQTL peaks observed in tumors, including asQTL peaks that were differentially imbalanced with respect to tumor-normal states. These data pinpointed putative causal regulatory elements at 20 GWAS loci, of which 11 were detected only in the tumor samples. More broadly, tumor-specific asQTLs were enriched for expression QTLs in benign tissues as well as accessible regions found in stem cells, supporting a hypothesis where some germline variants become reactivated during or after transformation and can be captured by epigenomic profiling of the tumor. Our study demonstrates the power of allele specificity in chromatin signals to uncover GWAS mechanisms, highlights the relevance of tumor-specific regulation in the context of cancer risk, and prioritizes multiple loci for experimental follow-up.

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer.

There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana-Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.

Prostate cancer reactivates developmental epigenomic programs during metastatic progression.

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions-from normal prostate epithelium to localized PCa to metastases-in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa are not created de novo; rather, they are prepopulated by the transcription factors FOXA1 and HOXB13 in normal prostate epithelium. Reprogrammed regulatory elements commissioned in metastatic disease hijack latent developmental programs, accessing sites that are implicated in prostate organogenesis. Analysis of reactivated regulatory elements enabled the identification and functional validation of previously unknown metastasis-specific enhancers at HOXB13, FOXA1 and NKX3-1. Finally, we observed that prostate lineage-specific regulatory elements were strongly associated with PCa risk heritability and somatic mutation density. Examining prostate biology through an epigenomic lens is fundamental for understanding the mechanisms underlying tumor progression.

Tumor fraction in cell-free DNA as a biomarker in prostate cancer.

BACKGROUND: Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non-tumor-derived cfDNA through multiple courses of therapy have not been well described. METHODS: CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy. RESULTS: TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1-3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non-tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was >7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic. CONCLUSION: TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response. TRIAL REGISTRATION: Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135. FUNDING: Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors.

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer.

BACKGROUND: Breast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. METHODS: A retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to carboplatin/docetaxel chemotherapy, defined according to a decline in prostate-specific antigen that exceeded 50% within 12 weeks of initiating this regimen. Associations between BRCA2 mutation status and response to carboplatin-based chemotherapy were tested using the Fisher exact test, with a 2-sided P value < .05 as the threshold for significance. RESULTS: Pathogenic germline BRCA2 variants were observed in 8 of 141 men (5.7%; 95% confidence interval, 2.5%-10.9%). Six of 8 BRCA2 carriers (75%) experienced prostate-specific antigen declines >50% within 12 weeks, compared with 23 of 133 noncarriers (17%; absolute difference, 58%; 95% confidence interval, 27%-88%; P < .001). Prostate cancer cell lines functionally corroborated these clinical findings. CONCLUSIONS: BRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer. Cancer 2017;123:3532-9. © 2017 American Cancer Society.