Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer.

BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. METHODS: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin-eligible patients with muscle-invasive bladder cancer to receive neoadjuvant durvalumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectomy alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. RESULTS: In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8% (95% CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2% (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P = 0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6% in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. CONCLUSIONS: Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. (Funded by AstraZeneca; NIAGARA ClinicalTrials.gov number, NCT03732677; EudraCT number, 2018-001811-59.).

Associations between T cell infiltration, T cell receptor clonality, histology and recurrence in renal cell carcinoma.

Renal cell carcinoma (RCC) is comprised of clear-cell (ccRCC) and non-clear-cell (nccRCC) tumors. Despite definitive surgical resection in localized disease, recurrence often occurs. A commercial method based on a multiplex polymerase chain reaction (PCR) assay exclusively targets rearranged T cell receptor (TCR) genes to generate high-throughput sequencing-based data, allowing characterization of the immune repertoire within tumors. In this study we performed a retrospective analysis on archived tumor samples from patients with recurring versus non-recurring T3 ccRCC and on samples from early nccRCC versus ccRCC. Following genomic DNA extraction and multiplex PCR, the fraction of T cells within tumors, the number of unique receptors ('richness') and their relative abundances ('clonality') were calculated. Statistical significance and correlations were calculated using Student's t-test and Spearman's rho, respectively. Average fraction and clonality of T cells in tumors from non-recurring patients was 2.5- and 4.3-fold higher than in recurring patients (P = 0.025 and P = 0.043, respectively). A significant positive correlation was found between T cell fraction and clonality (Spearman's rho = 0.78, P = 0.008). The average fraction of T cells in ccRCC tumors was 2.8-fold higher than in nccRCC tumors (P = 0.015). Clonality and estimated richness were similar between ccRCC and nccRCC tumors. In summary, recurrence of ccRCC is associated with a lower fraction and clonality of T cells within tumors; nccRCC tumors are more 'deserted' than ccRCC, but similar in their ability to generate a clonal T cell repertoire. Our work suggests associations between the characteristics of T cell infiltrate, histology and tumor recurrence.

Patient and clinician experience with a rapidly implemented large-scale video consultation program during COVID-19.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has forced health-care providers to find creative ways to allow continuity of care in times of lockdown. Telemedicine enables provision of care when in-person visits are not possible. Sheba Medical Center made a rapid transition of outpatient clinics to video consultations (VC) during the first wave of COVID-19 in Israel. OBJECTIVE: Results of a survey of patient and clinician user experience with VC are reported. METHODS: Satisfaction surveys were sent by text messages to patients, clinicians who practice VC (users) and clinicians who do not practice VC (non-users). Questions referred to general satisfaction, ease of use, technical issues and medical and communication quality. Questions and scales were based on surveys used regularly in outpatient clinics of Sheba Medical Center. RESULTS: More than 1200 clinicians (physicians, psychologists, nurses, social workers, dietitians, speech therapists, genetic consultants and others) provided VC during the study period. Five hundred and forty patients, 162 clinicians who were users and 50 clinicians who were non-users completed the survey. High level of satisfaction was reported by 89.8% of patients and 37.7% of clinician users. Technical problems were experienced by 21% of patients and 80% of clinician users. Almost 70% of patients but only 23.5% of clinicians found the platform very simple to use. Over 90% of patients were very satisfied with clinician's courtesy, expressed a high sense of trust, thought that clinician's explanations and recommendations were clear and estimated that the clinician understood their problems and 86.5% of them would recommend VC to family and friends. Eighty-seven percent of clinician users recognize the benefit of VC for patients during the COVID-19 pandemic but only 68% supported continuation of the service after the pandemic. CONCLUSION: Our study reports high levels of patient satisfaction from outpatient clinics VC during the COVID-19 pandemic. Lower levels of clinician satisfaction can mostly be attributed to technical and administrative challenges related to the newly implemented telemedicine platform. Our findings support the continued future use of VC as a means of providing patient-centered care. Future steps need to be taken to continuously improve the clinical and administrative application of telemedicine services.

ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

BACKGROUND: Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease. METHODS: We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis. RESULTS: The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor. CONCLUSIONS: Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.

Correction to: ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.

After the publication of the original article [1], we were notified the upper panel of the Fig. 1, where the patients' codes are listed, was cropped by mistake so the patients 1-8 are repeated.

A Retrospective Analysis of the Safety and Activity of Lutetium-177-Prostate-Specific Membrane Antigen Radionuclide Treatment in Older Patients with Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Prostate cancer is a common malignancy of the elderly, and with the aging of the population, the need is growing for therapies suitable for this age group. Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). In a recent single-arm phase II trial and a subsequent expansion cohort, a prostate-specific antigen (PSA) decline of ≥50% was observed in approximately 60% of patients receiving Lu-PSMA. Taking into account the specific challenges and potential toxicities of Lu-PSMA administration in elderly men, we sought to retrospectively analyze the safety and activity of Lu-PSMA in men aged older than 75 years with mCRPC. PATIENTS AND METHODS: The electronic medical records of 24 patients aged older than 75 years treated with Lu-PSMA "off-trial" were reviewed, and clinical data were extracted. Clinical endpoints were toxicity and activity, defined as a PSA decline ≥50%. Descriptive statistics were performed using Excel. RESULTS: The median age at treatment start was 81.7 years (range 75.1-91.9). The median number of previous treatment lines was four. The number of treatment cycles ranged from one to four; the mean administered radioactivity was 6 GBq per cycle. Treatment was generally tolerable; side effects included fatigue (n = 8, 33%), anemia (n = 7, 29%), thrombocytopenia (n = 5, 21%), and anorexia/nausea (n = 3, 13%). Clinical benefit was observed in 12 of 22 patients (54%); PSA decline above 50% was observed in 11 patients (48%) and was associated with significantly longer overall survival. CONCLUSION: Our results indicate that Lu-PSMA is safe and active in elderly patients with mCRPC. IMPLICATIONS FOR PRACTICE: Lutetium-177-prostate-specific membrane antigen (Lu-PSMA), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen, enabling beta particle therapy targeted to metastatic castration-resistant prostate cancer (mCRPC). The recently published single-arm phase II trial with Lu-PSMA, describing its safety and activity, did not include patients aged older than 75 years. In this study, Lu-PSMA activity was retrospectively analyzed in patients aged older than 75 years and results indicate that treatment was tolerable and similarly active in this age group, with no new emerging safety signals. Despite the small cohort size, this analysis suggests that Lu-PSMA can serve as an advanced palliative treatment line in mCRPC in elderly patients.

RCC Real-World Data: Prognostic Factors and Risk Stratification in the Immunotherapy Era.

Immunotherapy has transformed the landscape of treatment in metastatic renal cell carcinoma (mRCC) in the last decade. Currently, prognostic risk stratification is based on the model developed in the era of vascular endothelial growth factor receptor inhibitors (VEGFRi) by Heng in 2009. Our study aims to find the most relevant risk criteria for mRCC patients treated with checkpoint inhibitors (CPI). In a retrospective cohort study, laboratory, pathology, demographic, and clinical data were retrieved from electronic medical records of consecutive mRCC patients treated with CPI in a tertiary center between 2015 and 2020. An unbiased multivariate analysis was performed to define predictive variables with a bootstrap validation step. We analyzed data on 127 patients with a median follow-up of 60 months. The median overall survival (OS) since the diagnosis of metastatic disease was 57 months. The response rate for CPI was 39%. Five risk factors were correlated with worse OS: intact primary kidney tumor (HR 2.33, p = 0.012), liver metastasis (HR 3.33, p = 0.001),

Immune-Related Thyroiditis as a Predictor for Survival in Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (CPI) are indicated for metastatic renal cell carcinoma (mRCC). Immune-related thyroiditis (irT), an immune-related adverse event (irAE), affects up to 30% of patients. We aimed to determine whether irT is associated with overall survival in mRCC. A retrospective cohort study of 123 consecutive patients treated with CPI for mRCC in a single center between 2015 and 2020 was conducted. Disease risk stratification was assessed by two methods: Heng criteria and a novel dichotomic stratification system to "Low risk" versus "High risk" adding number of metastatic sites. Thirty-eight percent of patients developed irT. In the general cohort, irT was not associated with a survival benefit. However, irT was associated with better survival in the poor risk group per Heng criteria (n = 17, HR = 0.25, p = 0.04) and in the novel "High risk" group (HR = 0.28, n = 42, p = 0.01), including after accounting for covariates in multivariate analysis (HR = 0.27, p = 0.003). Having any irAE was associated with improved survival in the whole cohort, with no significant correlation of any specific irAE, in either the whole cohort or the "High risk" group. We conclude that irT is an early and prevalent irAE, associated with prolonged survival in patients with poor/"High" risk mRCC.

Response to Anti-PD1/L1 Antibodies in Advanced Urothelial Cancer in the 'Real-Life' Setting.

Immune checkpoint inhibitors (ICIs) are now the standard of care for metastatic urothelial carcinoma (mUC) patients. Our aim was to describe the activity of ICIs in mUC and find the clinical parameters associated with response. This is a retrospective, single-center chart review of mUC patients receiving ICIs. The overall survival (OS) was plotted using the Kaplan-Meier method and was compared using a log-rank test. Associations between the variables and responses were analyzed by univariate and multivariable analyses, using either logistic regression or a Chi-square/Fisher's exact test. Ninety-four patients received ICIs, 85% of which were in the second line or beyond; the median age was 71.8 years, and 82% were men. Six (6.4%), 11 (11.7%), 7 (7.4%) and 70 (74.5%) patients achieved a complete response (CR), partial response (PR), mixed response/stable disease (M/SD) or progressive disease (PD), respectively. The median overall survival was 3.2 months for the entire cohort and was significantly different according to the response pattern-not reached, 32.3, 6.4 and 2.0 months for CR, PR, M/SD and PD, respectively. The response was not significantly associated with the line of treatment. 'Site of metastasis' was associated with the response, and the absolute neutrophil count was borderline associated with the response. In summary, we found a substantial variance in the potential benefit from ICIs in mUC, emphasizing the need for predictive biomarkers and frequent monitoring of mUC patients receiving ICIs.

A real-world comparison of docetaxel versus abiraterone acetate for metastatic hormone-sensitive prostate cancer.

BACKGROUND: Docetaxel (D) or secondary hormonal therapy (SHT) each combined with androgen deprivation therapy (ADT) represent possible treatment options in males with metastasized hormone-sensitive prostate cancer (mHSPC). Real-world data comparing different protocols are lacking yet. Thus, our objective was to compare the efficacy and safety of abiraterone acetate (AA)+ADT versus D+ADT in mHSPC. METHODS: In a retrospective multicenter analysis including males with mHSPC treated with either of the aforementioned protocols, overall survival (OS), progression-free survival 1 (PFS1), and progression-free survival 2 (PFS2) were assessed for both cohorts. Median time to event was tested by Kaplan-Meier method and log-rank test. The Cox-proportional hazards model was used for univariate and multivariate regression analyses. RESULTS: Overall, 196 patients were included. The AA+ADT cohort had a longer PFS1 in the log-rank testing (23 vs. 13 mos., p < 0.001), a longer PFS2 (48 vs. 33 mos., p = 0.006), and longer OS (80 vs. 61 mos., p = 0.040). In the multivariate analyses AA+ADT outperformed D+ADT in terms of PFS1 (HR = 0.34, 95% CI = 0.183-0.623; p = 0.001) and PFS2 (HR = 0.33 95% CI = 0.128-0.827; p = 0.018), respectively, while OS and toxicity rate were similar between both groups. CONCLUSIONS: AA+ADT is mainly associated with a similar efficacy and overall toxicity rate as D+ADT. Further prospective research is required for validation of the clinical value of the observed benefit of AA+ADT for progression-free end-points.

Clinical Variables Associated with PSA Response to Lutetium-177-PSMA ([177Lu]-PSMA-617) Radionuclide Treatment in Men with Metastatic Castration-Resistant Prostate Cancer.

Lutetium-177-PSMA ([177Lu]-PSMA-617), a radiolabeled small molecule, binds with high affinity to prostate-specific membrane antigen (PSMA), enabling targeted radiation therapy to metastatic prostate lesions. Our objective was to retrospectively analyze the activity of [177Lu]-PSMA-617 given off-trial to men with metastatic castration resistant prostate cancer (mCRPC) and identify clinical factors associated with PSA response. Electronic medical records of all men treated with [177Lu]-PSMA-617 were reviewed and analyzed. Overall survival was calculated using the Kaplan-Meier method. The association between potential variables and PSA response was analyzed by univariate analysis, using either logistic regression or χ2/Fisher's exact test. Multivariable analysis was carried out using logistic regression on all categorical variables with a P-value of <0.1 on univariate analysis. Variables found to be statistically significant were then used to define a categorical score. A total of 52 patients received at least one cycle of [177Lu]-PSMA-617. Clinical benefit was observed in 28 patients (52%). PSA decline ≥20% and ≥50% was observed in 26 (50%) and 18 patients (35%), respectively. Achievement of any PSA decline at first measurement was significantly associated with survival. There was a negative association between the number of previous chemotherapy lines and PSA decline above 20%. Univariate analysis followed by multivariable analysis showed that older age and higher hemoglobin were significantly associated with a PSA decline >20%. A score combining these two parameters was significantly associated with PSA response. In summary, [177Lu]-PSMA-617 is active in the 'real-life' setting of heavily pretreated men with mCRPC.

Evaluation of tolerability and efficacy of incorporating carboplatin in neoadjuvant anthracycline and taxane based therapy in a BRCA1 enriched triple-negative breast cancer cohort.

PURPOSE: The addition of carboplatin (Cb) to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) has been demonstrated to improve pathologic complete response (pCR) at the expense of increased toxicity. We aimed to evaluate the effectiveness and tolerability of dose-dense anthracycline & cyclophosphamide (ddAC) followed by weekly paclitaxel (wT) in combination with weekly Cb. METHODS: Retrospective data was collected on patients with clinical stage I-III TNBC treated with neoadjuvant ddAC-wTCb (four cycles of ddA 60 mg/m2 and ddC 600 mg/m2 every 2 weeks followed by 12 cycles of wT 80 mg/m2 with Cb AUC 1.5). Indices of tolerability and pCR were evaluated and compared to a historical cohort (n = 76) treated with ddAC-T. A secondary objective was to evaluate the rates of pCR by BRCA status. RESULTS: For 43 eligible patients, mean age was 41.5 years, 51% had clinical stage II disease, 81.4% were clinically node positive and 32.6% carried a deleterious BRCA1 mutation. Only 35% completed all scheduled doses of chemotherapy. Grade 3/4 neutropenia was observed in 42.5% of patients. Overall pCR was 51.2%; 44.8% in BRCA wild-type compared to 64.3% in BRCA-associated TNBC (p = 0.232). pCR rates with ddAC-wTCb were similar to historic institutional rates with ddAC-T (51.2% vs. 51.3%, p = 0.987) and were comparable when stratified by BRCA status. In pooled multivariate analysis, only BRCA status (HR 4.00, 95%CI 1.65-9.75, p = 0.002) was significantly associated with pCR. CONCLUSION: Neoadjuvant ddAC-wTCb is less tolerable in clinical practice compared to most clinical trials, with a pCR comparable to historic rates using non-platinum regimen. The role of Cb in neoadjuvant chemotherapy for BRCA mutated TNBC remains uncertain.