Perspectives from neuro-oncology providers on patient access to electronic records: a survey study.

Aim: To evaluate the neuro-oncology providers' experience with patient online access to electronic records. Methods: Cross-sectional survey for physicians and advanced care providers within the field of neuro-oncology in the USA. Results: 65 providers completed the survey, from all major regions of the USA. 58% reported that at least once per month, patients contacted them outside of an office visit about provider notes or a laboratory or imaging finding accessed online. 54% of providers did not think that all laboratory results should be released automatically, and only 25% of providers thought that all radiology reads should be released immediately. 97% thought that some patients suffered substantial distress viewing test results prior to appointments. Qualitative responses aligned with the quantitative results. Conclusion: Most neuro-oncology providers are concerned about the immediate release of laboratory and imaging findings to patients without guidance.

Prior studies had investigated the perspectives of medical providers on patients having immediate access to medical records. However, almost none of them focus on neuro-oncology. In our study, we distributed a survey electronically to neuro-oncology providers across the USA to seek their perspectives. Our results show that most neuro-oncology providers found patients having immediate access to their records to be useful. However, they raised concerns about the immediate release of laboratory and imaging findings to patients without guidance. Our study also included free responses from the neuro-oncology providers that could help mitigate this concern.

Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing.

Introduction: Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 (BRCA1/2) via tumor-only profiling, then determined the germline testing outcomes for those patients. Methods: A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing. Results: This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing. Conclusion: Tumor-only testing is likely to identify P/LPVs in BRCA1/2. Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations.

Clinical characteristics and outcomes of phase I cancer patients with CCNE1 amplification: MD Anderson experiences.

Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients' initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m2, presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

PURPOSE: We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. EXPERIMENTAL DESIGN: We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. RESULTS: A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. CONCLUSIONS: ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

Characteristics and Outcome of AKT1 E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry.

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.See related commentary by Castellanos and Baxi, p. 490.

Identification of Actionable Genomic Alterations Using Circulating Cell-Free DNA.

PURPOSE: Cell-free DNA (cfDNA) next-generation sequencing is a noninvasive approach for genomic testing. We report the frequency of identifying alterations and their clinical actionability in patients with advanced/metastatic cancer. PATIENTS AND METHODS: Prospectively consented patients had cfDNA testing performed. Alterations were assessed for therapeutic implications. RESULTS: We enrolled 575 patients with 37 tumor types. Of these patients, 438 (76.2%) had at least one alteration detected, and 205 (35.7%) had one or more alterations of high potential for clinical action. In diseases with 10 or more patients enrolled, 50% or more had at least one alteration deemed of high potential for clinical action. Trials were identified in 80% of patients (286 of 357) with any alteration and in 92% of patients (188 of 205) with one or more alterations of high potential for clinical action of whom 57.6% (118 of 205) had 6 or more months of follow-up available. Of these patients, 10% (12 of 118) had received genomically matched therapy through enrollment in clinical trials (n = 8), off-label drug use (n = 3), or standard of care (n = 1). Although 88.6% of all patients had a performance status of 0 or 1 upon enrollment, the primary reason for not acting on alterations was poor performance status at next treatment change (28.1%; 27 of 96). CONCLUSION: cfDNA testing represents a readily accessible method for genomic testing and allows for detection of genomic alterations in most patients with advanced disease. Utility may be higher in patients interested in investigational therapeutics with adequate performance status. Additional study is needed to determine whether utility is enhanced by testing earlier in the treatment course.

Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis.

Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only ("other-only first metastasis"). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer.

PURPOSE: We sought to determine the significant genomic alterations in patients with metastatic breast cancer (MBC), and survival outcomes in common genotypes. PATIENTS AND METHODS: High-depth next generation sequencing was performed for 202 genes in tumor and normal DNA from 257 patients with MBC, including 165 patients with ER/PR+ HER2- (hormone receptor positive, HR+ positive), 32 patients with HER2+ and 60 patients with triple negative (ER/PR/HER2-) cancer. Kaplan Meier survival analysis was performed in our discovery set, in breast cancer patients analyzed in The Cancer Genome Atlas, and in a separate cohort of 98 patients with MBC who underwent clinical genomic testing. RESULTS: Significantly mutated genes (SMGs) varied by histology and tumor subtype, but TP53 was a SMG in all three subtypes. The most SMGs in HR+ patients included PIK3CA (32%), TP53 (29%), GATA3 (15%), CDH1 (8%), MAP3K1 (8%), PTEN (5%), TGFBR2 (4%), AKT1 (4%), and MAP2K4 (4%). TP53 mutations were associated with shorter recurrence-free survival (P=0.004), progression-free survival (P=0.00057) and overall survival (P=0.003). Further, TP53 status was prognostic among HR+ patients with PIK3CA mutations. TP53 mutations were also associated with poorer overall survival in the 442 HR+ breast cancer patients in the TCGA (P=0.042) and in an independent set of 96 HR+ MBC who underwent clinical sequencing (P=0.0004). CONCLUSIONS: SMGs differ by tumor subtype but TP53 is significantly mutated in all three breast cancer subtypes. TP53 mutations are associated with poor prognosis in HR+ breast cancer. TP53 mutations should be considered in the design and interpretation of precision oncology trials.

Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer.

BACKGROUND: Understanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations. METHODS: Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model. RESULTS: A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both). CONCLUSION: Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.

Physician interpretation of genomic test results and treatment selection.

BACKGROUND: Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results. METHODS: On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable. RESULTS: Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS). CONCLUSIONS: Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2018;124:966-72. © 2017 American Cancer Society.

Antiangiogenesis and gene aberration-related therapy may improve overall survival in patients with concurrent KRAS and TP53 hotspot mutant cancer.

PURPOSE: Genetic alterations such as activating KRAS and/or inactivating TP53 are thought to be the most common drivers to tumorigenesis. Therefore, we assessed phase I cancer patients with KRAS+/TP53+ mutations. RESULTS: Approximately 8% of patients referred to phase I clinical trials harbored concurrent KRAS and TP53 mutations. Patients who received a phase I trial therapy (n = 57) had a median OS of 12 months, compared with 4.6 months in those who were not treated (n = 106; p = 0.003). KRAS G13 and TP53 R273 mutations were associated with poor overall survival (OS), while antiangiogenesis and gene aberration-related therapies were associated with prolonged OS. A prognostic model using neutrophilia, thrombocytosis, hypoalbuminemia, body mass index <30 kg/m2, and the absence of lung metastasis was established and validated. Phase I cancer patients in the low-risk group had a median OS of 16.6 months compared with 5.4 months in the high-risk group (p < 0.001). Untreated patients in the low-risk group had a median OS of 6.7 months compared with 3.6 months in the high-risk group (p = 0.033). EXPERIMENTAL DESIGN: We analyzed 163 consecutive patients with advanced KRAS+/TP53+ mutant cancer who were referred to phase I clinical trials, to identify molecular aberrations, clinical characteristics, survivals, and potentially effective treatment regimens. CONCLUSIONS: This study provided preliminary evidence that besides modulation of the proinflammatory state, antiangiogensis and concomitant gene aberration-related therapies may improve the treatment of KRAS+/TP53+ mutant cancer.

Clinical outcomes based on multigene profiling in metastatic breast cancer patients.

BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Preoperative serum osteocalcin may predict postoperative elevated parathyroid hormone in patients with primary hyperparathyroidism.

BACKGROUND: Persistent postoperative elevation of parathyroid hormone (POePTH) following successful parathyroidectomy for primary hyperparathyroidism (PHPT) is presumed to result from bone remineralization. Predicting which patients may need treatment is difficult. This study investigated whether preoperative serum osteocalcin (OC), a bone turnover marker involved in mineralization, can predict POePTH. METHODS: A total of 198 patients (155 women and 43 men) with parathyroidectomy from November 2007 to October 2009 in MD Anderson Cancer Center, Houston, TX, USA, were included in our analysis. Separate multivariate regression models determined associations between preoperative OC and POePTH at 6 and 12 months postoperatively. Regression models were adjusted for demographics (age, gender, race, height, weight, BMI), preoperative BMD and bisphosphonate use, adenoma weight, serum levels of PTH, calcium, vitamin D, creatinine, and phosphate. Patients with baseline GFR <60 ml/min/1.73 m(2) and postoperative serum calcium >10.14 mg/dl at 6 and 12 months were excluded. RESULTS: Patients' mean age (±SD) was 60 (±14) years. POePTH (>80 pg/ml) occurred in 13 and 12% patients at 6 and 12 months, respectively. Preoperative serum creatinine and bisphosphonate use were positively associated with POePTH (p < 0.05) both at 6 and 12 months. Preoperative OC was predictive of POePTH (p < 0.05) at 6 months (ß 0.35; 95% confidence interval (CI), 0.11-0.58) and at 12 months (ß 0.79; 95% CI, 0.27-1.31). CONCLUSIONS: Preoperative OC may help to predict risk of POePTH in patients with PHPT. Research with longer follow-up in patients with no known baseline chronic kidney disease stratified by high versus normal preoperative serum creatinine is recommended.