Preparing Veterans Health Administration Psychologists to Meet the Complex Needs of Aging Veterans.

Background: There are significant workforce shortages for geriatric mental health care. The imbalance is particularly pronounced in the Veterans Health Administration (VHA) due to the large number of aging veterans receiving care. Workforce-based educational programs are needed to train existing clinicians to meet the mental health needs of aging veterans. Observations: This article describes an expansion of the Geriatric Scholars Program to train VHA psychologists to care for aging veterans. The multicomponent program includes an introductory course and opportunities to apply geriatric knowledge and skills through quality improvement initiatives. The Geriatric Scholars Program-Psychology Track evolved to incorporate ongoing specialized elective learning opportunities for scholars. A webinar series extends the educational programs to reach the entire VHA workforce. Conclusions: The Geriatric Scholars Program-Psychology Track represents a longitudinal educational approach to training VHA psychologists in clinical geropsychology. Other community-based organizations can use this model to construct and implement similar programs.

Enhancing specialty training in geropsychology competencies: An evaluation of a VA Geriatric Scholars Program advanced topics workshop.

There is a growing need for psychologists with specialized training in geriatric mental health competencies. The Geriatric Scholars Program for Psychologists (GSP-P) was created to address this shortage within a large integrated healthcare system. In 2019, GSP-P piloted an advanced workshop designed to enhance expertise in geriatric mental health competencies among graduates of its foundational competencies core course. The workshop included 3.5 days of expert-led seminars regarding the biopsychosocial needs of older adults with chronic medical illness and was followed by completion of an individualized learning plan. This paper describes the evaluation of the course using a mixed methods with data collected prior to the workshop, immediately post-workshop, and six months post-workshop. Results indicated enthusiasm for the workshop, significant improvements in four geropsychology domains on the Pikes Peak Geropsychology Knowledge and Skill Assessment Tool, and benefit from completion of the independent learning plans. Our findings demonstrate that continued enhancement of geropsychology competencies through advanced coursework is feasible and improves knowledge and skill, particularly when combined with individualized learning plans.

Usage of epidermal growth factor mutation testing and impact on treatment patterns in non-small cell lung cancer: An international observational study.

OBJECTIVES: Epidermal growth factor receptor (EGFR) mutations (EGFRm) are common oncogene drivers in non-small cell lung cancer (NSCLC). This real-world study explored treatment patterns and time to receive EGFRm test results in patients with advanced EGFRm NSCLC. METHODS: A cross-sectional medical chart review was completed May-August 2020 in Australia, Canada, Germany, Italy, South Korea, Taiwan, UK, and USA. Eligible patients had advanced NSCLC and a positive EGFRm test result January-December 2017. Data were abstracted from NSCLC diagnosis to end of follow-up (31 March 2020) or patient's death whichever occurred earlier. The index date was the date of EGFRm confirmation. RESULTS: 223 physicians provided data for 1,793 patients. Patients' mean age was 64.7 years, 54 % were male, 30.7 % had no history of smoking. Overall, 78 % of EGFRm test results were received ≤ 2 weeks after request (range of median 7-14 days across countries). Median time from advanced NSCLC diagnosis to EGFRm test result was 18 days (median range 10-22 days across countries). Over a third (37 %) of patients received a systemic treatment prior to EGFRm result; chemotherapy (25 %) and EGFR-TKI (15 %) were most commonly prescribed; post-EGFR test-result was EGFR-TKI (68 %); 80 % of patients initiated EGFR-TKI at any time point post-NSCLC diagnosis. Of those receiving a first-line EGFR-TKI post-EGFRm testing, 84 % received a TKI alone, 12 % in combination with chemotherapy, and 3 % with other treatments. Median time from first-line EGFR-TKI initiation post-EGFRm testing to first subsequent treatment was 19.8 months. CONCLUSION: Over one-fifth of patients wait >14 days for their EGFRm test results, affecting their likelihood of receiving first-line EGFR-TKI with 20 % of patients never receiving EGFR TKI treatment. There was significant inter-country variability in the proportion of patients receiving EGFR TKIs. Our study highlights the need to improve EGFRm testing turnaround times and treatment initiation across countries.

BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

Diet quality and exercise in older veterans with PTSD: a pilot study.

Older veterans with posttraumatic stress disorder (PTSD) are at increased risk of obesity and cardiometabolic disease. Physical activity and healthy eating are two behaviors that impact health, functional independence, and disease risk in later life, yet few studies have examined the relationship between PTSD and diet quality. This secondary analysis aimed to: (a) characterize the diet quality of older veterans with PTSD in comparison to U.S. dietary guidelines and (b) explore if participation in a supervised exercise intervention spurred simultaneous changes in dietary behavior. Diet quality was assessed with the Dietary Screener Questionnaire (DSQ), which measures daily intake of fiber, calcium, added sugar, whole grain, dairy, and fruits/vegetables/legumes. The sample included 54 military veterans ≥ 60 years old with PTSD who participated in a randomized controlled pilot trial comparing 12 weeks of supervised exercise (n = 36) to wait-list usual care (n = 18). The DSQ was administered at baseline and 12 weeks. Consumption of added sugar exceeded U.S. dietary guideline recommendations and consumption of whole grains, fruits/vegetables/legumes, fiber, calcium, and dairy fell short. Participation in the supervised exercise intervention was not associated with changes in diet quality. Results revealed that the diet quality of older veterans with PTSD is poor, and while the exercise intervention improved health through exercise, it did not make veterans any more likely to adopt a more healthful diet. Interventions targeting diet, or diet + exercise, are needed to manage the increased risk of obesity and cardiometabolic disease present in older veterans with PTSD.

Older veterans with posttraumatic stress disorder (PTSD) are at risk for several physical health conditions that reduce their quality of life. Physical activity and healthy eating are important behaviors for promoting good health and physical function in later life. The purpose of this study was to examine the diet quality of older veterans with PTSD and explore whether a program designed to increase exercise also improved diet. Diet quality was measured with a self-report survey, the Dietary Screener Questionnaire (DSQ), which measures daily intake of fiber, calcium, added sugar, whole grain, dairy, and fruits/vegetables/legumes. Study participants were 54 military veterans age 60 years and older with PTSD who participated in a randomized controlled pilot trial comparing 12 weeks of supervised exercise to wait-list usual care. The DSQ was administered at baseline and 12 weeks post intervention. Results show that older veterans with PTSD have overall poor diet quality that included consuming too much added sugar and not enough whole grains, fruits/vegetables/legumes, fiber, calcium, and dairy. Participation in the supervised exercise did not lead to simultaneous diet quality changes over 12 weeks. This study shows that diet quality is poor in older veterans with PTSD and future programs are needed to target this health behavior.

Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors.

BACKGROUND: The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment. CASE PRESENTATION: Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLCNOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0-4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases - including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis. CONCLUSIONS: CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis.

Clinical types of checkpoint inhibitor-related pneumonitis in lung cancer patients: a multicenter experience.

BACKGROUND: Checkpoint inhibitor-related pneumonitis (CIP) is not well classified according to clinical factors. We propose different clinical sub-types of CIP based on clinical factors and investigated the corresponding clinical features, treatments, and outcomes. METHODS: We conducted a multicenter retrospective study of patients with lung cancer (including non-small cell lung cancer and small cell lung cancer) who developed CIP. The clinical characteristics, radiologic features, treatments, and outcomes of CIP were analyzed. RESULTS: A total of 55 patients developed CIP and were classified into 3 groups as follows: 21 in the pure type (PT) group, 14 in the induced type (IT) group, and 20 in the mixed type (MT) group. The incidence of severe (grade 3-5) pneumonitis was significantly higher in the IT group than in the PT and MT groups (71.4% vs. 14.3% vs. 50.0%, P=0.002). Antiviral therapy was significantly more frequent in the IT group than in the PT and MT groups. Antibiotic therapy was administered in 23.8%, 71.4%, and 80.0% of patients with the PT, IT, and MT, respectively. The improvement time in the PT group was longer than that in the IT and MT groups (0.9 vs. 0.5 vs. 0.3 months, P=0.028). Patients with the PT had a better tumor response to immune checkpoint inhibitors (ICIs) than those with the other 2 types [overall response rate (ORR), 78% vs. 31% vs. 44%, P=0.027]. CONCLUSIONS: The clinical classification of CIP may favor strategies for treatments and predict the tumor response to ICIs.

Improving Geropsychology Competencies of Veterans Affairs Psychologists.

Older adults are more likely to seek mental health care through integrated care settings such as primary care. Currently, there exists a significant shortage of mental health providers trained in geropsychology and integrated care competencies. To address this need within the Veterans Health Administration, a national workforce development program was extended to include psychologists, which is called the Geriatric Scholars Program-Psychology Track (GSP-P). The GSP-P has two overarching educational program aims: (1) to improve geropsychology competencies of practicing VA psychologists, particularly those working within integrated settings (e.g., primary care) and (2) enrich psychologists' abilities to enact change in their clinical settings. Ninety-eight VA clinicians participated in the GSP-P, which includes a multi-day in-person course, from 2014 to 2018. Participants completed measures assessing confidence and self-reported knowledge in geropsychology and integrated care competencies pre-course and 3-months post-completion. Two-weeks post-course participants responded to open-ended survey questions regarding their perceptions of the course and potential applications of learning. Significant improvements in confidence in and knowledge of geropsychology and integrated care competencies emerged from pre-course to 3-months post-completion. Qualitative findings demonstrated that participants valued the face-to-face, integrated multimodal educational program. Findings provided insights regarding clinicians' planned application of the knowledge acquired, such as modifying treatments for older patients. Specialized workforce programs such as the GSP-P have a significant, positive impact on the care of older Veterans.

Development and initial validation of the Hopelessness Inventory for Later Life (HILL).

OBJECTIVES: Hopelessness is associated with depression, physical illness, and mortality. It is a key risk factor for suicidality in later life. Limitations have been identified in available hopelessness assessment measures regarding their use with older adults. The current study describes the development and initial psychometric evaluation of a content-valid, self-report scale for late-life hopelessness (i.e. the Hopelessness Inventory for Later Life; HILL). METHODS: A sample of 265 older adults (ages 60-99, M = 71.1, SD = 6.7) was recruited through a combination of in-person, online, and mailed solicitations. Participants completed a survey battery containing the preliminary HILL and measures of related constructs (e.g. depression, anxiety, suicide risk, social support) to examine its psychometric properties. RESULTS: Multiple analytic item selection strategies resulted in two viable versions of the scale: the HILL and the HILL-Shortened (HILL-S). Both exhibited strong item response characteristics and preliminary evidence of unidimensionality (via factor analysis), internal consistency (α = .96 and α = .89, respectively), and construct validity (via correlations with related constructs). CONCLUSION: Findings provide preliminary psychometric support for both the HILL and HILL-S. Advantages for use of the HILL and the HILL-S over existing measures of hopelessness are discussed.

Qualitative Analysis of a Supervised Exercise Program for Older Veterans With PTSD.

OBJECTIVE: Older veterans with post-traumatic stress disorder (PTSD) experience substantial physical and mental health challenges. Given the well-known and wide-reaching benefits of exercise, exploring the impact of interventions designed specifically for this population would be valuable. As such, the present study explored perspectives from older veterans with PTSD who participated in Warrior Wellness, a 12-week supervised exercise intervention designed for older veterans with PTSD. This study was aimed at evaluating 1) facilitators of engagement, 2) perceived benefits from the intervention, and 3) recommendations about possible modifications to the intervention. DESIGN: Qualitative study. SETTING: Face-to-face semistructured interviews conducted after the Warrior Wellness trial was completed. PARTICIPANTS: Fifteen veterans (100% male, 93% African American or Black, 100% non-Hispanic or Latinx, average age = 68.7 years) who completed the Warrior Wellness exercise program. MEASUREMENTS: Semistructured interviews were conducted using an interview guide that assessed veterans' experience in Warrior Wellness and recommendations for future intervention modifications. Interviews were subsequently transcribed and analyzed by thematic analysis. RESULTS: Shared experience, program features, camaraderie during workouts, and accountability emerged as facilitators of engagement. Perceived benefits spanned physical health, mental health, and behavioral domains. Finally, veterans provided several suggestions for modifying the intervention such as increasing its duration, adding a nutritional component, and including significant others in enrollment. CONCLUSIONS: This study offers valuable insights into the intervention and interpersonal factors that veterans view as important for their engagement in exercise, the perceived benefits of exercise, and the ways in which interventions designed for this population can be refined.

Pan-Cancer Analysis of BRCA1 and BRCA2 Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity.

PURPOSE: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations (BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non-BRCA1/2-associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear. METHODS: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS: BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non-BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non-BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency (BRCA1/2-associated cancers, 8.9%; non-BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION: Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.

Retrospective analysis of real-world data to determine clinical outcomes of patients with advanced non-small cell lung cancer following cell-free circulating tumor DNA genomic profiling.

OBJECTIVES: Liquid biopsy and comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) are increasingly used for detection of targetable genomic alterations (GA) in non-small cell lung cancer (NSCLC). To examine the clinical outcomes for patients following CGP using liquid biopsy versus tissue biopsy, receipt of matched targeted therapy post-CGP and associated outcomes were evaluated in the real-world setting. METHODS: 6491 patients with NSCLC and liquid biopsy (N = 937 tests) and/or tissue (N = 5582 tests) CGP were included in a de-identified commercial clinico-genomic database. Targetable GAs included National Comprehensive Cancer Network NSCLC guideline biomarkers. Clinical characteristics, real-world progression, and real-world response (rwR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports. RESULTS: At the time of liquid biopsy CGP, 53% (496/937) of patients were documented to have received ≥1 line of prior therapy (tissue CGP: 13%, 735/5582). 90% (832/928) of liquid biopsy cases had evidence of ctDNA. A targetable GA was detected in 20% (188/937) of liquid biopsy and 22% (1215/5582) of tissue CGP cases. Use of matched targeted therapy overall was similar post-liquid biopsy or post-tissue CGP but varied considerably across emerging (25%, 79/317) versus standard of care (SOC) (74%, 475/640) GA. Real-world-progression free survival for patients receiving SOC first line matched targeted therapy administered following liquid biopsy (n = 33) and tissue (n = 229) CGP were similar (13.8 vs 10.6 months; aHR = 0.68 [0.36-1.26]). Among patients evaluated for rwR, overall response rate (partial/complete response) to matched targeted therapy post-liquid biopsy CGP was 75% (39/52) versus 66% post-tissue CGP (254/385, P = 0.51). CONCLUSION: Retrospective analysis of real-world clinico-genomic data demonstrated that clinical outcomes on matched targeted therapy were similar following liquid biopsy and tissue CGP in NSCLC, which suggests routine clinical use of liquid biopsy CGP can reliably guide therapy selection.

Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial.

Importance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. Design, Setting, and Participants: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months). Interventions: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device. Main Outcomes and Measures: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Results: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). Conclusions and Relevance: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02101385.

Germline and somatic DNA repair gene alterations in prostate cancer.

BACKGROUND: Emerging evidence has suggested that DNA repair gene alterations may be important in prostate cancer pathogenesis. In the current study, the authors sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors with attention to tissue distribution as well as specific genomic alterations. METHODS: The authors studied the distribution and type of alterations in 24 genes that are considered important for DNA repair in 944 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 287 or 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer. Captured libraries were sequenced to a median exon coverage depth of >×500. Specific genomic alterations were characterized and the frequencies of mutations by tissue site (prostate vs metastases) were compared using logistic regression. RESULTS: A total of 152 patients from the cohort of 944 men (16%) harbored a germline or somatic mutation in ≥1 DNA repair genes. The most frequently mutated genes were BRCA2 (11.4%) and ATM (5.8%), followed by MSH6 (2.5%) and MSH2 (2.1%). Mutations were identified in approximately 20.1% of primary prostate tumors compared with 18.8% of bone metastases. When stratified by tissue site, the highest rates of DNA repair mutations were found in solid organ metastases, including brain and visceral metastases, compared with prostate. CONCLUSIONS: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral and other solid organ metastases appear enriched for these mutations compared with localized tumors or bone and lymph node metastases.

Improving the Gender-Affirmation Process for Transgender and Gender-Nonconforming Individuals: Associations Among Time Since Transition Began, Body Satisfaction, and Sexual Distress.

Sexual distress is associated with a variety of negative outcomes. Unique contributors to sexual distress exist among transgender individuals. The current study examined the impacts of gender-affirming interventions (i.e., hormone therapy [HT], gender-affirmation surgery [GAS]) and body satisfaction on sexual distress among 317 transgender adults recruited nationally to participate in an anonymous online survey. As expected, individuals who had received HT and/or GAS reported better body satisfaction compared to those who wanted these interventions but had not yet received them. Sexual distress did not differ by transition status. As hypothesized, time since transition began was positively associated with body satisfaction, and there was an indirect relationship between time since transition began and sexual distress through body satisfaction. These results replicated findings in the extant literature suggesting that body satisfaction is improved by GAS. Furthermore, this was the first study of which we are aware to examine the role of time since transition began with respect to body satisfaction and the resulting impact on sexual distress. Results from this study may have clinical implications that could help improve the gender-affirmation experience for transgender individuals.

Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy.

BACKGROUND: Liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor DNA (ctDNA) to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of a sequenced tissue sample obtained from the same tumor. The clinical utility study (CUS) for the FoundationACT™ ctDNA assay (Foundation Medicine, Cambridge, MA, USA; NCT02620527) is a multi-center prospective clinical study for multiple solid tumor types to compare genomic profiling of paired tissue and blood samples from the same patient. In this subset of the study, paired specimens from 96 patients with colorectal cancer (CRC) were analyzed with comprehensive genomic profiling (CGP) of the tumor tissue sample (FoundationOne®) and blood sample (FoundationACT™). METHODS: Both samples underwent CGP using the hybrid capture-based Illumina Hi-Seq technology. Maximum somatic allele frequency (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both tumor and liquid were compared for each subject. RESULTS: Among these patients, 61% were male; 74% had clinical stage IV disease, 19% had clinical stage III disease, and 7% had clinical stage II disease. Time between the tissue biopsy and liquid biopsy (range, 0-709 days) had a significant impact on the positive percent agreement (PPA) between the two assays. Eighty percent of cases had evidence of ctDNA in the blood (MSAF >0). For all cases with MSAF >0, 171 base substitutions and insertions/deletions (indels) were identified in the tumor, and 79% (PPA) of these identical alterations were also identified in matched ctDNA samples; PPA increased to 87% for cases <270 days between the tissue and liquid biopsy, 95% for <90 days, and 100% PPA for <30 days. All known and likely short variants in KRAS, NRAS, and BRAF were analyzed independently as testing of these genes is recommended by the National Comprehensive Cancer Network (NCCN) for patients with CRC and have therapeutic implications. For NCCN genes, PPA was 80% for all time points for short variants; PPA increased to 90% for cases <270 days between the tissue and liquid biopsy. There was high concordance for KRAS G12X between tissue and liquid: overall percent agreement (97%), PPA (93%), negative percent agreement (NPA) (100%), positive predictive value (PPV) (100%), and negative predictive value (NPV) (96%) for the <270 day cohort. CONCLUSIONS: In cases where tumor tissue profiling is not possible, these results provide compelling evidence that genomic profiling of ctDNA in late stage CRC shows a high concordance with tumor tissue sequencing results and can be used to identify most clinically relevant alterations capable of guiding therapy for these patients.

Molecular testing strategies in non-small cell lung cancer: optimizing the diagnostic journey.

Molecular testing identifies patients with advanced non-small cell lung cancer (NSCLC) who may benefit from targeted therapy or immunotherapy (i.e., immune checkpoint inhibitor treatment for patients with high tumor mutational burden (TMB), microsatellite instability-high or mismatch repair-deficient tumors). Current guidelines state that molecular testing should be conducted at the time of initial diagnosis and tumor progression on targeted therapy. In real-world clinical practice in the United States (US), molecular testing is often not conducted or happens late in the diagnostic journey, resulting in delayed or inappropriate treatment. Herein, we review the rationale for molecular testing in advanced NSCLC, along with best-practice guidelines based on published recommendations and our own clinical experience, including a case study. We propose three strategies to optimize molecular testing in newly diagnosed patients with advanced NSCLC: (I) pulmonologists, interventional radiologists, or thoracic surgeons order molecular tests as soon as advanced NSCLC with an adenocarcinoma component is suspected; (II) liquid biopsies conducted early in the diagnostic pathway; and (III) pathologist-directed reflex testing, as conducted in other areas of oncology. To help facilitate these strategies, we outline our recommendations for optimal sample collection techniques and stewardship. In summary, we believe that implementation of these individual strategies will allow clinicians to effectively leverage available treatment options for advanced NSCLC, reducing the time to optimal treatment and improving patient outcomes.

MET Genomic Alterations in Head and Neck Squamous Cell Carcinoma (HNSCC): Rapid Response to Crizotinib in a Patient with HNSCC with a Novel MET R1004G Mutation.

Identification of effective targeted therapies for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains an unmet medical need. A patient with platinum-refractory recurrent oral cavity HNSCC underwent comprehensive genomic profiling (CGP) that identified an activating MET mutation (R1004). The patient was treated with the oral MET tyrosine kinase inhibitor crizotinib with rapid response to treatment.Based on this index case, we determined the frequency of MET alterations in 1,637 HNSCC samples, which had been analyzed with hybrid capture-based CGP performed in the routine course of clinical care. The specimens were sequenced to a median depth of >500× for all coding exons from 182 (version 1, n = 24), 236 (version 2, n = 326), or 315 (version 3, n = 1,287) cancer-related genes, plus select introns from 14 (version 1), 19 (version 2), or 28 (version 3) genes frequently rearranged in cancer. We identified 13 HNSCC cases (0.79%) with MET alterations (4 point mutation events and 9 focal amplification events). MET-mutant or amplified tumors represent a small but potentially actionable molecular subset of HNSCC. KEY POINTS: This case report is believed to be the first reported pan-cancer case of a patient harboring a MET mutation at R1004 demonstrating a clinical response to crizotinib, in addition to the first documented case of head and neck squamous cell carcinoma (HNSCC) with any MET alteration responding to crizotinib.The positive response to MET inhibition in this patient highlights the significance of comprehensive genomic profiling in advanced metastatic HNSCC to identify actionable targetable molecular alterations as current treatment options are limited.

A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability-High Cases in 67,000 Patient Samples.

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.

Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors.

PURPOSE: Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability. METHODS: Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]). RESULTS: Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors. CONCLUSION: Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.