Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: BRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss. OBJECTIVE: To evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Differences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models. RESULTS AND LIMITATIONS: We identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2-1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2-1.6; p < 0.001). CONCLUSIONS: Copy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and "CTC-only" losses. BRCA2 losses were supported by increases in genomic instability. PATIENT SUMMARY: Current testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.

Clinical annotations for prostate cancer research: Defining data elements, creating a reproducible analytical pipeline, and assessing data quality.

BACKGROUND: Routine clinical data from clinical charts are indispensable for retrospective and prospective observational studies and clinical trials. Their reproducibility is often not assessed. We developed a prostate cancer-specific database for clinical annotations and evaluated data reproducibility. METHODS: For men with prostate cancer who had clinical-grade paired tumor-normal sequencing at a comprehensive cancer center, we performed team-based retrospective data collection from the electronic medical record using a defined source hierarchy. We developed an open-source R package for data processing. With blinded repeat annotation by a reference medical oncologist, we assessed data completeness, reproducibility of team-based annotations, and impact of measurement error on bias in survival analyses. RESULTS: Data elements on demographics, diagnosis and staging, disease state at the time of procuring a genomically characterized sample, and clinical outcomes were piloted and then abstracted for 2261 patients (with 2631 samples). Completeness of data elements was generally high. Comparing to the repeat annotation by a medical oncologist blinded to the database (100 patients/samples), reproducibility of annotations was high; T stage, metastasis date, and presence and date of castration resistance had lower reproducibility. Impact of measurement error on estimates for strong prognostic factors was modest. CONCLUSIONS: With a prostate cancer-specific data dictionary and quality control measures, manual clinical annotations by a multidisciplinary team can be scalable and reproducible. The data dictionary and the R package for reproducible data processing are freely available to increase data quality and efficiency in clinical prostate cancer research.

Spine Pain and Metastatic Prostate Cancer: Defining the Contribution of Nonmalignant Etiologies.

PURPOSE: In patients with metastatic prostate cancer (MPC), the contribution of nonmalignant etiologies to morbidity is often overlooked. METHODS: We retrospectively reviewed the documented specialist assessments of back pain in men with MPC in a joint medical oncology and physiatry clinic at our tertiary cancer care center. Data on cancer disease extent, hormonal status, sites of spread, pain characteristics, physiatric examination findings, imaging, and recommended management were reviewed, extracted, and codified. For those with back pain at a site of known disease, pain etiology was classified as malignant, nonmalignant, or mixed. RESULTS: Ninety-three men were collaboratively assessed for back pain, 24 (26%) with a biochemical recurrence and 69 (74%) with MPC of whom 53 (77%) reported pain in an area of known spinal metastases including 35 (66%) metastatic castration-resistant disease and 34 (64%) a precancer history of back pain. The presenting pain symptoms of the 53 patients were activity-related in 22 (42%), radicular in eight (15%), transitional movement-related in seven (13%), biologic in five (9%), and multifactorial in 11 (21%). Overall, pain was deemed malignant in 20 (38%; five castration-sensitive, 15 metastatic castration resistant prostate cancer), nonmalignant in 12 (23%; four castration-sensitive, eight CRPC), and of mixed etiology in 21 (40%; nine castration-sensitive, 12 CRPC). CONCLUSION: Nonmalignant etiologies contributed significantly to back pain at sites of metastatic spread for 33/53 (62%) patients with MPC assessed by medical oncology and physiatry. We recommend multidisciplinary care for patients with MPC and back pain to address nonmalignant etiologies that contribute to functional compromise.

Metastatic gastroesophageal cancer in older patients - is this patient cohort represented in clinical trials?

BACKGROUND: Older patients are underrepresented in the clinical trials that determine the standards of care for oncological treatment. We conducted a review to identify whether there have been age-restrictive inclusion criteria in clinical trials over the last twenty five years, focusing on patients with metastatic gastroesophageal cancer. METHODS: A search strategy was developed encompassing Embase, PubMed and The Cochrane Library databases. Completed phase III randomised controlled trials evaluating systemic anti-cancer therapies in metastatic gastroesophageal malignancies from 1st January 1995 to 18th November 2020 were identified. These were screened for eligibility using reference management software (Covidence; Veritas Health Innovation Ltd). Data including age inclusion/exclusion criteria and median age of participants were recorded. The percentage of patients ≥ 65 enrolled was collected where available. The change over time in the proportion of studies using an upper age exclusion was estimated using a linear probability model. RESULTS: Three hundred sixty-three phase III studies were identified and screened, with 66 trials remaining for final analysis. The majority of trials were Asian (48%; n = 32) and predominantly evaluated gastric malignancies, (86%; n = 56). The median age of participants was 62 (range 18-94). Thirty-two percent (n = 21) of studies specified an upper age limit for inclusion and over half of these were Asian studies. The median age of exclusion was 75 (range 65-80). All studies prior to 2003 used an upper age exclusion (n = 12); whereas only 9 that started in 2003 or later did (17%). Among later studies, there was a very modest downward yearly-trend in the proportion of studies using an upper age exclusion (-0.02 per year; 95%CI -0.05 to 0.01; p = 0.31). Fifty-two percent (n = 34) of studies specified the proportion of their study population who were ≥ 65 years. Older patients represented only 36% of the trial populations in these studies (range 7-60%). CONCLUSIONS: Recent years have seen improvements in clinical trial protocols, with many no longer specifying restrictive age criteria. Reasons for poor representation of older patients are complex and ongoing efforts are needed to broaden eligibility criteria and prioritise the inclusion of older adults in clinical trials.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

BACKGROUND: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. METHODS: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. RESULTS: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. CONCLUSION: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Seek and Find: Current Prospective Evidence for Prostate-specific Membrane Antigen Imaging to Detect Recurrent Prostate Cancer.

CONTEXT: Men with biochemically relapsed prostate cancer face a clinical conundrum. Depending on the detected distribution of disease, treatment goals may range from cure with focal therapy to palliative with systemic therapy to expectant observation. Retrospective studies of prostate-specific membrane antigen (PSMA)-based imaging demonstrate higher disease detection rates than conventional imaging. OBJECTIVE: This review focuses on available prospective evidence for diagnostic use of PSMA-based imaging to accurately restage recurrent prostate cancer and explores the potential clinical impact, near future uses, and challenges for PSMA-based imaging in this setting. EVIDENCE ACQUISITION: PubMed and EMBASE databases were searched for prospective studies with primary, secondary, or exploratory endpoints evaluating PSMA-based imaging for patients with recurrent prostate cancer published in English in the past 10 yrs. EVIDENCE SYNTHESIS: We reviewed 48 prospective studies evaluating the role of PSMA positron emission tomography (PET) in recurrent prostate cancer. These studies establish the diagnostic accuracy and safety of PSMA PET using the 68Ga-PSMA-11 and 18F-DCFPyL radiotracers even at lower prostate-specific antigen (PSA) levels (0.5 ≤ PSA < 1.0 ng/m: disease detection rate 51-78%). The use of PSMA PET has been shown to result in changes in management in up to two-thirds of patients. CONCLUSIONS: There is now higher-level regulatory-quality prospective evidence for PSMA-based imaging for the detection of recurrent prostate cancer. There is prospective evidence of superiority over cross-sectional imaging and bone scintigraphy, as well as for the alterations in disease management as a result of PSMA-based imaging. PATIENT SUMMARY: When the prostate-specific antigen (PSA) level is rising after primary therapy, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is excellent at detecting and localizing prostate cancer, even at low PSA levels. Those who benefit best from treatment modifications based on PSMA PET findings are yet to be defined.

Prevalence of Insomnia in an Oncology Patient Population: An Irish Tertiary Referral Center Experience.

BACKGROUND: The NCCN Guidelines for Survivorship recommend dedicated sleep assessment. Reported insomnia prevalence in the general Irish population is 6% to 15%. Reported insomnia prevalence internationally among new/recently diagnosed patients with cancer varies from 30.9% to 54.3%. Insomnia prevalence has not been previously quantified in an Irish oncology cohort. METHODS: A 40-item questionnaire was prospectively administered to ambulatory patients with cancer aged ≥18 years. Prespecified criteria to define insomnia syndrome combined those of the International Classification of Sleep Disorders, version 1, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A) was used to screen for potential confounding variables. RESULTS: The response rate to the questionnaire was 87% (294/337). The predominant respondent age group was 55 to 64 years (26%; 77/294), 70.7% were female (208/294), and the most common cancer subtypes were breast (37.4%), colorectal (12.9%), and lung (12.2%). A total of 62% (183/294) of patients reported sleep disturbance after diagnosis, 63% (115/183) reported moderate/severe distress related to this disturbance, and 37% (61/183) reported a significant impact on physical function. Although 33% (98/294) met insomnia syndrome criteria, only 34% (33/98) of these patients had a preexisting history of sleep disturbance. Female sex, age <65 years, cancer subtype, alcohol consumption, and HADS-D/A ≥11 were associated with statistically significant higher odds ratios (OR) of insomnia syndrome. Multivariate analysis identified breast cancer (OR, 3.17; P=.01), age <65 years (OR, 1.8; P=.03), and alcohol consumption (OR, 2.3; P=.005) as independent predictors of insomnia syndrome. CONCLUSIONS: Insomnia syndrome prevalence in this cohort is comparable to that reported previously and supports dedicated sleep assessment. This study identifies potentially modifiable risk factors for insomnia and demonstrates additional utility of the HADS score in identifying patients at risk.

Similar overall survival with reduced vs. standard dose bevacizumab monotherapy in progressive glioblastoma.

INTRODUCTION: Bevacizumab has demonstrated activity in glioblastoma (GBM), but the true benefits and optimal dose-schedule are debated. A lower dose-schedule than standard-dose bevacizumab (10 mg/kg 2-weekly) might offer similar benefits with lower costs. At our Institution, patients are randomly assigned at time of primary diagnosis to Neuro-Oncologists, who have varying practices in terms of bevacizumab dose-schedule upon progression. METHODS: In a retrospective analysis we examined overall survival (OS), measured from first administered bevacizumab dose until death, according to dose-schedule. Patients with de novo WHO Grade IV GBM who received standard- or reduced-dose (5 mg/kg 2-weekly) bevacizumab were included. MGMT methylation status and time from diagnosis to bevacizumab start were examined as prognostic variables. Clinical benefit and a comparative cost analysis were assessed. RESULTS: In total, 1127 bevacizumab doses were administered to 118 patients [Median: 7, Range: 1-44]. Median OS (mOS) was 5.8 months. 69 (59%) patients received standard-dose bevacizumab (mOS: 5.97 months) and 49 patients received reduced-dose (mOS: 5.7 months). No statistically significant difference in OS between dosing schedule was seen (HR: 1.11, P-value: .584). Patients with MGMT methylated tumors (43%) had improved OS compared to those with unmethylated tumors; 7.03 vs 4.97 months (HR: 0.61, P-value: .027). If all patients were treated with reduced-dose bevacizumab, an estimated €2.4M cost reduction would be observed. CONCLUSIONS: In this retrospective study, reduced-dose bevacizumab schedule resulted in similar OS to standard-dose bevacizumab monotherapy with substantial cost savings. MGMT methylation appears to convey a survival benefit in the setting of bevacizumab treatment for progressive GBM.

PI3K inhibition to overcome endocrine resistance in breast cancer.

INTRODUCTION: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. AREAS COVERED: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. EXPERT OPINION: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

Adding Pertuzumab to Trastuzumab and Taxanes in HER2 positive breast cancer.

INTRODUCTION: The monoclonal antibody trastuzumab has improved the median disease free and overall survival of patients with early stage breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). Despite this advance, some patients experience cancer relapse and novel approaches are always needed. One such advance is the monoclonal antibody pertuzumab, which prevents dimerisation between members of the HER family of transmembrane glycoprotein receptors. AREAS COVERED: In this review, the authors analyse recent research which has focused on the development of new HER2 targeting agents for HER2-positive breast cancer, particularly pertuzumab, and its addition to trastuzumab and taxanes. EXPERT OPINION: Pertuzumab has significantly improved disease control in patients with advanced HER2 positive breast cancer when added to chemotherapy and trastuzumab. Although pertuzumab has also increased response rates in the preoperative setting, this has not yet translated into increased overall survival. The authors believe that future research should focus on improvements in novel biomarkers to select patients for new treatments.