Publications by authors named "Andrea Necchi"

281 Publications

Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

Lancet Oncol 2022 Jan 11. Epub 2022 Jan 11.

Department of Cancer Medicine, INSERM U981, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study.

Methods: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597.

Findings: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths.

Interpretation: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(21)00660-4DOI Listing
January 2022

Exposure-response relationship of ramucirumab in RANGE, a randomized phase III trial in advanced urothelial carcinoma refractory to platinum therapy.

Br J Clin Pharmacol 2022 Jan 13. Epub 2022 Jan 13.

Yale University School of Medicine, New Haven, CT, USA.

Aims: Patients with advanced urothelial carcinoma (UC) who progress after platinum-based chemotherapy have a poor prognosis, and there is a medical need to improve current treatment options. Ramucirumab plus docetaxel significantly improved progression-free survival but not overall survival (OS) in platinum-refractory advanced UC (RANGE trial; NCT02426125). Here, we report the exposure-response (ER) of ramucirumab plus docetaxel using data from the RANGE trial.

Methods: Pharmacokinetic (PK) samples were collected (cycle 1-3, 5 ,9 [day 1] and 30 days from treatment discontinuation), and PK data were analyzed using population PK (popPK) analysis. The minimum ramucirumab concentration after first dose administration (C ; or trough concentration immediately prior to the second dose) was derived by popPK analysis and used as the exposure parameter for ER analysis. Cox proportional hazards regression models and matched case-control analyses were used to evaluate the relationship between C and OS. C relationship with safety was assessed descriptively.

Results: Several poor prognostic factors (ECOG 1; hemoglobin concentration <100 g/L, and presence of liver metastases) appeared more frequently in the lower exposure quartiles; suggesting a possible disease-PK interaction. A significant association was identified between C and OS (P = 0.0108). Higher exposure quartiles were associated with longer survival and smaller hazard ratios compared to placebo. No new exposure-safety trends were observed within the exposure range (ramucirumab 10mg/kg once every three weeks).

Conclusions: This prespecified ER analyses suggests a positive relationship between efficacy and ramucirumab exposure, with an imbalance associated with disease prognostic factors. Further investigation may elucidate possible disease-PK relationship.
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http://dx.doi.org/10.1111/bcp.15233DOI Listing
January 2022

Role of Bone Metastases in Patients Receiving Immunotherapy for Pre-Treated Urothelial Carcinoma: The Multicentre, Retrospective Meet-URO-1 Bone Study.

Clin Genitourin Cancer 2021 Dec 16. Epub 2021 Dec 16.

Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Considerable numbers of patients with metastatic urothelial carcinoma (mUC) develop bone metastases (BoM). Their impact on the efficacy of immune-checkpoint inhibitors (ICIs) is not yet investigated.

Methods: Between July 2014 and August 2020 data on pts treated with single-agent ICIs after failure of at least 1 previous line of chemotherapy for advanced disease, were retrospectively collected across 14 Italian centers. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method. Cox regression analysis was performed evaluating potential prognostic factors for OS and PFS. Each factor was evaluated in univariable (UVA) and multivariable analysis (MVA).

Results: A total of 208 evaluable patients treated with ICIs were identified, including 122 (59%) without BoM (BoM-) and 86 (41%) with bone metastases (BoM+). After a median follow-up of 22.3 months, BoM+ patients showed shorter OS (median 3.9 vs 7.8 months, HR 1.59 [95%CI, 1.15-2.20], P = .005) and shorter PFS (median 2.0 vs 2.6 months, HR 1.76 [95%CI, 1.31-2.37], P < .001). Probability of being alive was 62% vs 40% after 6 months, 38% vs 23% after 1 year and 24% vs 13% after 2 years, in BoM- and BoM+ respectively. Within each Bellmunt score, OS and PFS of BoM+ patients were shorter. Both presence of BoM and higher Bellmunt risk score were significantly associated with shorter OS and PFS in UVA and MVA.

Conclusion: Patients treated with single-agent ICIs for BoM+ mUC have a dismal prognosis compared to BoM-. Further research is needed to understand the mechanism behind these outcomes.
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http://dx.doi.org/10.1016/j.clgc.2021.12.008DOI Listing
December 2021

Cytoreductive Nephrectomy in 2021: Obsolete but Necessary.

Eur Urol Open Sci 2022 Feb 29;36:41-43. Epub 2021 Dec 29.

Unit of Urology, IRCCS Ospedale San Raffaele, Milan, Italy.

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http://dx.doi.org/10.1016/j.euros.2021.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724938PMC
February 2022

A global approach to improving penile cancer care.

Nat Rev Urol 2021 Dec 22. Epub 2021 Dec 22.

Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Rare tumours such as penile carcinoma have been largely neglected by the urology scientific community in favour of more common - and, therefore, more easily fundable - diseases. Nevertheless, penile cancer represents a rising burden for health-care systems around the world, because a lack of widespread expertise, ineffective centralization of care and absence of research funds have hampered our ability to improve the global care of these patients. Moreover, a dichotomy has arisen in the field of penile cancer, further impeding care: the countries that are mainly supporting research on this topic through the development of epidemiological studies and design of clinical trials are not the countries that have the highest prevalence of the disease. This situation means that randomized controlled trials in developed countries often do not meet the minimum accrual and are intended to close before reaching their end points, whereas trials are almost completely absent in those areas with the highest disease prevalence and probability of successful recruitment, such as Africa, South America and South Asia. The scientific and organizational inaction that arises owing to this mismatch translates into a burdensome cost for our patients. A global effort to gather experts and pull together scientific data from around the world may be the best way to boost clinical research, to change clinical practice and, ultimately, to improve care for patients and their families.
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http://dx.doi.org/10.1038/s41585-021-00557-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693593PMC
December 2021

Upper Tract Urothelial Carcinoma in the Lynch Syndrome Tumour Spectrum: A Comprehensive Overview from the European Association of Urology - Young Academic Urologists and the Global Society of Rare Genitourinary Tumors.

Eur Urol Oncol 2021 Dec 9. Epub 2021 Dec 9.

Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland; Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

Context: Upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy in Lynch syndrome (LS).

Objective: To systematically review the available literature focused on incidence, diagnosis, clinicopathological features, oncological outcomes, and screening protocols for UTUC among LS patients.

Evidence Acquisition: Medline, Scopus, Google Scholar, and Cochrane Database of Systematic Reviews were searched up to May 2021. Risk of bias was determined using the modified Cochrane tool. A narrative synthesis was undertaken.

Evidence Synthesis: Overall, 43 studies between 1996 and 2020 were included. LS patients exhibited a 14-fold increased risk of UTUC compared with the general population, which further increased to 75-fold among hMSH2 mutation carriers. Patients younger than 65 yr and patients with personal or family history of LS-related cancers should be referred to molecular testing on tumour specimen and subsequent genetic testing to confirm LS. Newly diagnosed LS patients may benefit from a multidisciplinary management team including gastroenterologist and gynaecologist specialists, while genetic counselling should be recommended to first-degree relatives (FDRs). Compared with sporadic UTUC individuals, LS patients were significantly younger (p = 0.005) and exhibited a prevalent ureteral location (p = 0.01). Radical nephroureterectomy was performed in 75% of patients (5-yr cancer-specific survival: 91%). No consensus on screening protocols for UTUC was achieved: starting age varied between 25-35 and 50 yr, while urinary cytology showed sensitivity of 29% and was not recommended for screening.

Conclusions: Urologists should recognise patients at high risk for LS and address them to a comprehensive diagnostic pathway, including molecular and genetic testing. Newly diagnosed LS patients should be referred to a multidisciplinary team, while genetic counselling should be recommended to FDRs.

Patient Summary: In this systematic review, we analysed the existing literature focused on upper tract urothelial carcinoma (UTUC) among patients with Lynch syndrome (LS). Our purpose is to provide a comprehensive overview of LS-related UTUC to reduce misdiagnosis and improve patient prognosis.
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http://dx.doi.org/10.1016/j.euo.2021.11.001DOI Listing
December 2021

Bladder-sparing combination treatments for muscle-invasive bladder cancer: A plea for standardized assessment and definition of clinical trials endpoints.

Urol Oncol 2021 Nov 25. Epub 2021 Nov 25.

Department of Medical Oncology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy.

Radical cystectomy is the standard of care for muscle invasive bladder cancer, although it represents a surgical procedure with high complication and mortality burden. Thus, more and more emphasis has been placed in favor of alternative treatments especially for patients who are unfit for or aim to avoid radical cystectomy. In this context, preclinical studies highlighted that chemoradiation therapy (CRT) may have immunomodulatory properties on tumor microenvironment with a consequent increase in immune biomarkers. Thus, following the encouraging results reached by immune checkpoint inhibitors (ICIs) in both metastatic and localized disease, CRT and ICIs combination treatment gained momentum as bladder-sparing option and several clinical trials were recently launched both as concurrent and sequential treatments. A narrative review of the literature was performed to summarize the rationale and clinical outcomes of trials testing CRT and ICIs combination. Promising results were recently released mainly from phase II trials reporting clinal complete response rates from 48% to 83%. Moreover, combination treatment, both as concurrent and sequential schedules, appeared to be quite tolerable. However, interpretation of preliminary findings is made difficult due to the heterogeneity of clinical endpoints among trials, patient population included and different measurement of response to treatment. Novel bladder-sparing strategies are finally gaining momentum in bladder cancer treatment. Despite preliminary findings are encouraging, harmonization of terminology and definition of clinical endpoints among trials will be mandatory to correctly assess the potential role of CRT and immunotherapy combination as bladder-sparing solution in routine clinical practice.
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http://dx.doi.org/10.1016/j.urolonc.2021.10.012DOI Listing
November 2021

Immunotherapy and Sonpavde score validation in advanced upper tract urothelial carcinoma: a retrospective study by the Italian Network for Research in Urologic-Oncology (Meet-URO group).

Immunotherapy 2022 02 17;14(2):107-114. Epub 2021 Nov 17.

Medical Oncology Unit, University Hospital of Parma, Parma, Italy.

Few data are available regarding the effectiveness of immune checkpoint inhibitors in advanced upper tract urothelial carcinoma (UTUC) patients. To provide a real-world experience with anti-PD-1/PD-L1-based therapy in UTUC patients, we involved an Italian network in a multicenter retrospective analysis. A total of 78 UTUC patients were enrolled. The median follow-up was 25.1 months. The median progression-free survival (mPFS) was 2.2 months (95% CI 1.8-2.6), and the median OS (mOS) was 6.0 months (95% CI 3.6-8.4). The Sonpavde score (including performance status > 0, hemoglobin < 10 g/dl, liver metastases, time from prior chemotherapy ≥ 3 months) split the patients into three groups (0 vs 1 vs 2-4 factors), efficiently predicting the OS and PFS outcome at the multivariate analyses (p < 0.0001). The prognosis of unselected UTUC patients is still unsatisfactory. The Sonpavde score was validated for the first time in an UTUC population, as a useful tool for the treatment decision-making process.
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http://dx.doi.org/10.2217/imt-2021-0109DOI Listing
February 2022

Von Hippel-Lindau disease-associated renal cell carcinoma: a call to action.

Curr Opin Urol 2022 Jan;32(1):31-39

Division of Experimental Oncology, Department of Urology, URI - Urological Research Institute.

Purpose Of Review: While the molecular and genetic bases of Von Hippel-Lindau (VHL) disease have been extensively investigated, limited evidence is available to guide diagnosis, local or systemic therapy, and follow-up. The aim of the current review is to summarize the ongoing trials both in preclinical and clinical setting regarding VHL disease management.

Recent Findings: Although genotype/phenotype correlations have been described, there is considerable inter and intra-familiar heterogeneity in VHL disease. Genetic anticipation has been reported in VHL disease. From a clinical point of view, expert-opinion-based protocols suggest testing those patients with any blood relative of an individual diagnosed with VHL disease, those with at least 1 or more suggestive neoplasms or patients presenting with clear cell renal cell carcinoma (ccRCC) diagnosed at a less than 40 years old, and/or multiple ccRCC. Clinical research is focused on safety and efficacy of systemic agents for patients with VHL-related ccRCC, with the aim to possibly preserve kidney function and improve patient survival.

Summary: To date, preclinical and clinical research on the topic is scarce and clinical guidelines are not supported by strong validation studies.
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http://dx.doi.org/10.1097/MOU.0000000000000950DOI Listing
January 2022

Patients with Muscle-Invasive Bladder Cancer with Nonluminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy.

J Urol 2021 Oct 13:101097JU0000000000002261. Epub 2021 Oct 13.

Department of Urology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with nonmetastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5%-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC.

Materials And Methods: Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan-Meier curves. Cox proportional hazards models were used to evaluate the primary and secondary study end points of overall survival (OS) and cancer-specific survival, respectively.

Results: A total of 601 patients with MIBC were included, of whom 247 had been treated with NAC and RC, and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and cancer-specific survival at 3 years was 7% and 5%, respectively. After controlling for clinicopathological variables, nonluminal tumors had greatest benefit from NAC, with 10% greater OS at 3 years (71% vs 61%), while luminal tumors had minimal benefit (63% vs 65%) for NAC vs non-NAC.

Conclusions: In patients with MIBC, a commercially available molecular subtyping assay revealed nonluminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.
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http://dx.doi.org/10.1097/JU.0000000000002261DOI Listing
October 2021

Fighting the 'tobacco epidemic' - A call to action to identify Targeted Intervention Points (TIPs) for better counseling patients with urothelial cancer.

Urol Oncol 2021 Dec 8;39(12):793-796. Epub 2021 Oct 8.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The association between tobacco use and urothelial cancer of the bladder is well known. Given the worsening tobacco epidemic, here we make the case for systematic targeted points of intervention for urologists and other professionals to intervene against bladder cancer. Awareness of contemporary checkpoints where we can intervene for counseling patients may help medical education in a tobacco-pandemic difficult setting.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.025DOI Listing
December 2021

Lynch syndrome in urological practice: diagnosis, therapeutic strategies, and screening for upper tract urothelial carcinoma.

Curr Opin Urol 2022 Jan;32(1):40-47

University Vita-Salute San Raffaele.

Purpose Of Review: To provide a comprehensive overview of diagnosis, treatment, and screening for upper tract urothelial carcinoma (UTUC) among Lynch syndrome patients.

Recent Findings: Lynch syndrome is an autosomal dominant disorder resulting from the germline mutation in the mismatch repair (MMR) system. The Lynch syndrome predisposes to early onset of a broad spectrum of tumours, among which UTUC represents the third most frequent malignancy. Since up to 10% of UTUC can be attributed to Lynch syndrome, a correct recognition of this disease provides the opportunity for patients and their relatives to be properly treated for UTUC and to be followed up for other Lynch syndrome-related malignancies.

Summary: UTUC patients less than 65 years, or UTUC patients with personal history of Lynch syndrome-related cancer, or with one first-degree relative (FDR) less than 50 years with Lynch syndrome-related cancer, or two FDRs with Lynch syndrome-related cancer regardless of age should be referred to molecular testing and subsequent DNA sequencing to confirm Lynch syndrome diagnosis. Considering the increased risk of metachronous recurrence, treatments other than radical nephroureterectomy, such as ureteroscopic laser ablation may represent valuable therapeutic strategies. As Lynch syndrome patients exhibit an approximate 14-fold increased risk of developing UTUC compared with general population, expert recommendations are urgently required in order to point out appropriate screening protocols.
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http://dx.doi.org/10.1097/MOU.0000000000000936DOI Listing
January 2022

Risk factors and survival outcomes for upstaging after inguinal lymph node dissection for cN1 penile squamous cell carcinoma.

Urol Oncol 2021 Dec 30;39(12):838.e7-838.e13. Epub 2021 Sep 30.

Department of Genitourinary Oncology, H Lee Moffitt Cancer Center, Tampa, FL.

Objectives: To identify incidence and risk factors for upstaging from cN1 to pN2/N3 at inguinal lymphadenectomy (ILND) for penile cancer (pSCC). Our secondary objective is to assess survival outcomes and associations for cN1 patients undergoing ILND.

Subjects/patients And Methods: Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND and had complete data were identified in a multi-institutional international cohort from 8 referral centers in 7 countries diagnosed from 1980 to 2017. Upstaging was defined as pN2/N3 at ILND. Multivariable logistic regression analysis was used to determine associations with upstaging, and Cox multivariable logistic regression analysis to determine associations with overall survival (OS).

Results: Of 144 patients were included in the final study population. 84 patients (58%) were upstaged from cN1 to pN2/N3, and 25 (17%) were down staged to pN0. Upstaging was associated with pT3/T4 (OR 4.1, 95%CI 1.5-11.7, P < 0.01) and pTX (OR 7.1, 95CI 1.6-51.1, P = 0.02). Age, smoking status, HPV status, and LVI were not associated with upstaging. Age (HR 1.03/y, 95%CI 1.01-1.06, P < 0.01) and upstaging (HR 2.8, 95%CI 1.3-5.9, P < 0.01) were associated with worse OS. Upstaged patients had a 5-year OS of 49%, compared with 86% for patients who were not upstaged.

Conclusion: The majority of cN1 pSCC patients harbor a higher-risk disease state than their clinical staging suggests, especially those with higher pT stages. More intensive pre-operative workup may be warranted for these patients to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.028DOI Listing
December 2021

Outcomes of men with HIV and germ cell cancer: Results from an international collaborative study.

Cancer 2022 Jan 30;128(2):260-268. Epub 2021 Sep 30.

ICH Study Center, Hamburg, Germany.

Background: Previous studies have shown that men with HIV and germ cell cancer (HIV-GCC) have inferior overall survival (OS) in comparison with their HIV-negative counterparts. However, little information is available on treatments and outcomes of HIV-GCC in the era of combination antiretroviral therapy (cART).

Methods: This study examined men living with HIV who were 18 years old or older and had a diagnosis of histologically proven germ cell cancer (GCC). The primary outcomes were OS and progression-free survival (PFS).

Results: Data for 89 men with a total of 92 HIV-GCCs (2 synchronous GCCs and 1 metachronous bilateral GCC) were analyzed; among them were 64 seminomas (70%) and 28 nonseminomas (30%). The median age was 36 years, the median CD4 T-cell count at GCC diagnosis was 420 cells/µL, and 77% of the patients on cART had an HIV RNA load < 500 copies/mL. Stage I disease was found in 44 of 79 gonadal GCCs (56%). Among 45 cases with primary disseminated GCC, 78%, 18%, and 4% were assigned to the good-, intermediate-, and poor-prognosis groups, respectively, of the International Germ Cell Cancer Collaborative Group. Relapses occurred in 14 patients. Overall, 12 of 89 patients (13%) died. The causes of death were refractory GCC (n = 5), an AIDS-defining illness (n = 3), and other causes (n = 4). After a median follow-up of 6.5 years, the 5- and 10-year PFS rates were 81% and 73%, respectively, and the 5- and 10-year OS rates were 91% and 85%, respectively.

Conclusions: The 5- and 10-year PFS and OS rates of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients.

Lay Summary: Men living with HIV are at increased risk for germ cell cancer (GCC). Previous studies have shown that the survival of men with HIV-associated germ cell cancer (HIV-GCC) is poorer than the survival of their HIV-negative counterparts. This study examined the characteristics, treatments, and outcomes of 89 men with HIV-GCC in the era of effective combination antiretroviral therapies. The long-term outcomes of men with HIV-GCC were similar to those reported for men with HIV-negative GCC. Patients with HIV-GCC should be managed identically to HIV-negative patients.
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http://dx.doi.org/10.1002/cncr.33928DOI Listing
January 2022

Can Negative Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Avoid the Need for Pelvic Lymph Node Dissection in Newly Diagnosed Prostate Cancer Patients? A Systematic Review and Meta-analysis with Backup Histology as Reference Standard.

Eur Urol Oncol 2021 Sep 17. Epub 2021 Sep 17.

Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Context: The role of positron emission tomography/computed tomography (PET/CT) with prostate-specific membrane antigen (PSMA) in the primary staging for patients with prostate cancer (PCa) is still debated.

Objective: To analyze published studies reporting the accuracy of PSMA PET/CT for detecting lymph node invasion (LNI) at pelvic lymph node dissection (PLND).

Evidence Acquisition: A search of PubMed/MEDLINE, Cochrane library's Central, EMBASE and Scopus databases, from inception to May 2021, was conducted. The primary outcome was to evaluate the sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of PSMA PET/CT in detecting LNI on a per-patient level. As a secondary outcome, NPV of PET PSMA was tested on a per-node-level analysis. Detection rates were pooled using random-effect models. Preplanned subgroup analyses tested the diagnostic accuracy after stratification for the preoperative risk group. PPV and NPV variation over LNI prevalence was evaluated. Only studies including extended PLND (ePLND) as the reference standard test were included.

Evidence Synthesis: Twenty-seven studies, with a total of 2832 participants, were included in quantitative synthesis. The sensitivity, specificity, PPV, and NPV of PSMA PET/CT for LNI were, respectively, 58% (95% confidence interval [CI] 50-66%), 95% (95% CI 93-97%), 79% (95% CI 72-85%), and 87% (95% CI 84-89%), with overall moderate heterogeneity between studies. At bivariate analysis, the diagnostic accuracy of PSMA PET/CT estimated through summary receiver operating characteristic-derived area under the curve was 84% (95% CI 81-87%). On a per-node level, NPV of PET PSMA was 97% (95% CI 96-99%). At subgroup analyses, according to preoperative risk groups, sensitivity, specificity, PPV, and NPV were 51%, 93%, 73%, and 81%, respectively, in high-risk patients. Over the LNI prevalence range of 5-40%, PPV increased from 59% to 91%, while NPV decreased from 99% to 84%.

Conclusions: PSMA PET/CT scan provides promising accuracy in the field of primary nodal staging for PCa. The high NPV in men with a lower risk of LNI might be clinically useful to reduce the number of unnecessary PLND procedures performed. Conversely, in high-risk patients, negative PSMA PET/CT cannot replace staging ePLND.

Patient Summary: In this systematic review and meta-analysis, we demonstrated that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) scan may optimize the primary nodal staging and surgical management of prostate cancer patients candidate to radical prostatectomy. The high negative predictive value in men with a lower risk of lymph node invasion might be clinically useful for reducing the number of useless pelvic lymph node dissection (PLND) procedures performed. Conversely, in high-risk patients, negative PSMA PET/CT cannot allow avoiding of PLND.
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http://dx.doi.org/10.1016/j.euo.2021.08.001DOI Listing
September 2021

Contemporary Outcomes of Patients With Nonmuscle-Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin: Implications for Clinical Trial Design. Letter.

J Urol 2021 12 29;206(6):1528. Epub 2021 Aug 29.

Division of Oncology, Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.

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http://dx.doi.org/10.1097/JU.0000000000002237DOI Listing
December 2021

Outcomes of metastatic urothelial carcinoma following discontinuation of enfortumab-vedotin.

Clin Genitourin Cancer 2021 Aug 14. Epub 2021 Aug 14.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address:

Background: Enfortumab vedotin (EV) is approved to treat metastatic urothelial carcinoma (mUC) following platinum and PD1/L1 inhibitors. Since the outcomes and patterns of therapy of patients following discontinuation of EV are unknown, we conducted a retrospective study to assess this issue.

Methods: Data were retrospectively obtained from patients with mUC following discontinuation of EV after prior platinum-based chemotherapy and PD1/L1 inhibitors. Objective response rate (ORR) was evaluated in those who received therapy post-EV. Statistical analyses were performed to describe the overall survival (OS) and compare patient characteristics and outcomes of those who did or did not receive treatment post-EV.

Results: Data were available for 63 patients from 6 institutions: 46 (73%) were male and median age was 68 years (range 43-83). The median OS was 32 weeks. Thirty-two patients (51%) received therapy after EV. The OS of those who did vs. did not receive post-EV therapy was significantly different (median 43.1 vs. 16.9 weeks, P = .015). Longer duration of prior EV therapy was associated with receipt of post-EV therapy (P = .0437) as well as OS in both the treated (P = .045) and untreated groups (P = .012). Objective response was observed in 3 of 32 patients (9.4%) who received therapy post-EV.

Conclusion: Outcomes of patients with mUC following discontinuation of EV are dismal and only 51% received therapy after discontinuation of EV. This study identifies benchmarks for the interpretation of activity of new agents following EV and raises the hypothesis for duration of EV as a potential prognostic factor following discontinuation of EV.
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http://dx.doi.org/10.1016/j.clgc.2021.08.002DOI Listing
August 2021

Causal contributors to tissue stiffness and clinical relevance in urology.

Commun Biol 2021 08 26;4(1):1011. Epub 2021 Aug 26.

Division of Experimental Oncology/Unit of Urology, URI, IRCCS San Raffaele Hospital, Milan, Italy.

Mechanomedicine is an emerging field focused on characterizing mechanical changes in cells and tissues coupled with a specific disease. Understanding the mechanical cues that drive disease progression, and whether tissue stiffening can precede disease development, is crucial in order to define new mechanical biomarkers to improve and develop diagnostic and prognostic tools. Classically known stromal regulators, such as fibroblasts, and more recently acknowledged factors such as the microbiome and extracellular vesicles, play a crucial role in modifications to the stroma and extracellular matrix (ECM). These modifications ultimately lead to an alteration of the mechanical properties (stiffness) of the tissue, contributing to disease onset and progression. We describe here classic and emerging mediators of ECM remodeling, and discuss state-of-the-art studies characterizing mechanical fingerprints of urological diseases, showing a general trend between increased tissue stiffness and severity of disease. Finally, we point to the clinical potential of tissue stiffness as a diagnostic and prognostic factor in the urological field, as well as a possible target for new innovative drugs.
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http://dx.doi.org/10.1038/s42003-021-02539-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390675PMC
August 2021

Survival Outcomes After Immediate Radical Cystectomy Versus Conservative Management with Bacillus Calmette-Guérin Among T1 High-grade Micropapillary Bladder Cancer Patients: Results from a Multicentre Collaboration.

Eur Urol Focus 2021 Aug 18. Epub 2021 Aug 18.

Department of Urology, Spedali Civili di Brescia, Brescia, Italy.

Background: Literature lacks clear evidence regarding the optimal treatment for non-muscle-invasive micropapillary bladder cancer (MPBC) due to its rarity and the presence of only small sample size and single-centre studies.

Objective: To assess cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and conservative management among T1 high-grade (HG) MPBC.

Design, Setting, And Participants: We retrospectively analysed a multicentre dataset including 119 T1 HG MPBC patients treated between 2005 and 2019 at 15 tertiary referral centres. The median follow-up time was 35 mo (interquartile range: 19-64).

Intervention: Patients underwent immediate RC versus conservative management with bacillus Calmette-Guérin.

Outcomes Measurements And Statistical Analysis: Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. Multivariable Cox analyses were performed to assess independent predictors of disease recurrence and disease progression after conservative management; covariates consisted of pure MPBC, concomitant lymphovascular invasion (LVI), and carcinoma in situ at initial diagnosis.

Results And Limitations: Immediate RC and conservative management were performed in 27% and 73% of patients, respectively. CSM and OM did not differ significantly among patient treated with immediate RC versus conservative management (Pepe-Mori test p = 0.5 and log-rank test p = 0.9, respectively). Overall, 66.7% and 34.5% of patients experienced disease recurrence and disease progression after conservative management, respectively. At multivariable Cox analyses, concomitant LVI was an independent predictor of disease recurrence (p = 0.01) and progression (p = 0.03), while pure MPBC was independently associated with disease progression (p = 0.03). The absence of a centralised re-review and the retrospective design represent the main limitations of our study.

Conclusions: Conservative management could achieve satisfactory results among T1 HG MPBC patients with neither pure MPBC nor LVI at initial diagnosis.

Patient Summary: Bacillus Calmette-Guérin seems to be an effective therapy for T1 micropapillary bladder cancer patients with neither pure micropapillary disease nor lymphovascular invasion at initial diagnosis.
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http://dx.doi.org/10.1016/j.euf.2021.07.015DOI Listing
August 2021

Contrasting genomic profiles from metastatic sites, primary tumors, and liquid biopsies of advanced prostate cancer.

Cancer 2021 Dec 11;127(24):4557-4564. Epub 2021 Aug 11.

Upstate Medical University, State University of New York, Syracuse, New York.

Background: This study assessed the contrasting genomic profiles from the primary tumors (PTs), metastatic (MET) sites, and circulating tumor DNA (ctDNA) of patients with prostate cancer (PC).

Methods: A total of 1294 PC tissue specimens and 2462 ctDNA specimens underwent hybrid capture-based comprehensive genomic profiling (CGP). Specimens included tissue from PTs; MET biopsies from bone, liver (LIV), lung (LU), brain (BN), lymph node, and soft tissue sites; and ctDNA.

Results: Differences in alteration frequencies between PT, MET, and ctDNA specimens for selected genes were observed. TMPRSS2:ERG fusion frequencies were similar between PTs and MET sites (35% vs 33%) but varied among MET sites. Genomic alterations (GAs) in AR were lowest in PTs (2%) and highest in MET sites (from 24% in LU to 50% in LIV). BN had the highest genomic alterations/tumor (8) and enrichment for PTEN GAs. The BRCA2 GA frequency varied from 0% in BN to 15% in LIV. ERBB2 amplification was increased in MET sites in comparison with PTs. RB1 GAs were increased in LIV. Biomarkers potentially associated with an anti-PD(L)1 response included CDK12 GAs (16% in LU) and a microsatellite instability-high status (29% in BN). Analyses of ctDNA featured a broad spectrum of GAs similar to those detected across MET sites.

Conclusions: CGP of PTs, MET sites, and ctDNA in PC exhibited differences most likely associated with tumor progression, clonal evolution, and exposure to systemic therapies; ctDNA can also capture a broad range of potential therapeutic opportunities for patients with PC.
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http://dx.doi.org/10.1002/cncr.33865DOI Listing
December 2021

Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease.

Oncologist 2021 12 17;26(12):1026-1034. Epub 2021 Aug 17.

Department of Medicine, University of Washington, Seattle, Washington, USA.

Background: Fit patients with metastatic urothelial carcinoma (mUC) receive first-line platinum-based combination chemotherapy (fPBC) as standard of care and may receive additional later-line chemotherapy after progression. Our study compares outcomes with subsequent platinum-based chemotherapy (sPBC) versus subsequent non-platinum-based chemotherapy (sNPBC).

Materials And Methods: Patients from 27 international centers in the Retrospective International Study of Cancers of the Urothelium (RISC) who received fPBC for mUC and at least two cycles of subsequent chemotherapy were included in this study. A multivariable Cox proportional hazards model compared overall survival (OS) and progression-free survival (PFS).

Results: One hundred thirty-five patients received sPBC and 161 received sNPBC. Baseline characteristics were similar between groups, except patients who received sPBC had higher baseline hemoglobin, higher disease control rate with fPBC, and longer time since fPBC. OS was superior in the sPBC group (median 7.9 vs 5.5 months) in a model adjusting for comorbidity burden, performance status, liver metastases, number of fPBC cycles received, best response to fPBC, and time since fPBC (hazard ratio, 0.72; 95% confidence interval, 0.53-0.98; p = .035). There was no difference in PFS. More patients in the sPBC group achieved disease control than in the sNPBC group (57.4% vs 44.8%; p = .041). Factors associated with achieving disease control in the sPBC group but not the sNPBC group included longer time since fPBC, achieving disease control with fPBC, and absence of liver metastases.

Conclusion: After receiving fPBC for mUC, patients who received sPBC had better OS and disease control. This may help inform the choice of subsequent chemotherapy in patients with mUC.

Implications For Practice: Patients with progressive metastatic urothelial carcinoma after first-line platinum-based combination chemotherapy may now receive immuno-oncology agents, erdafitinib, enfortumab vedotin, or sacituzumab govitecan-hziy; however, those ineligible for these later-line therapies or who progress after receiving them may be considered for subsequent chemotherapy. In this retrospective study of 296 patients, survival outcomes and disease control rates were better in those receiving subsequent platinum-based rechallenge compared with non-platinum-based chemotherapy, suggesting that patients should receive platinum rechallenge if clinically able. Disease control with platinum rechallenge was more likely with prior first-line platinum having achieved disease control, longer time since first-line platinum, and absence of liver metastases.
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http://dx.doi.org/10.1002/onco.13925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649023PMC
December 2021

Neoadjuvant Immunotherapy: The Next Gold Standard Before Radical Surgery for Urothelial Cancer.

Eur Urol Open Sci 2021 Aug 21;30:34-36. Epub 2021 Jun 21.

Medical Oncology Department, IRCCS Ospedale San Raffaele, Milan, Italy.

Cisplatin-based chemotherapy followed by radical cystectomy with bilateral pelvic lymph-node dissection is the current standard for cT2-4a N0 M0 urothelial bladder cancer. Immune checkpoint inhibitors have recently been tested in the neoadjuvant setting with promising pathological and survival results and a better safety profile. Excellent pathological responses have been observed, especially in cases with higher clinical T stage and PD-L1 expression, in addition to patients with selected gene signatures. In biomarker-selected patients, this manageable approach has the potential to become a new treatment option in the near future.

Patient Summary: For patients with bladder cancer invading the bladder wall muscle, platinum-based chemotherapy has been the standard treatment. Increasing evidence suggests that an alternative first treatment for this disease could be immunotherapy. Novel biomarkers and further studies are needed to support this approach before it can be used in everyday clinical practice.
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http://dx.doi.org/10.1016/j.euros.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317828PMC
August 2021

Postoperative Chemotherapy Bladder Instillation After Radical Nephroureterectomy: Results of a European Survey from the Young Academic Urologist Urothelial Cancer Group.

Eur Urol Open Sci 2020 Dec 6;22:45-50. Epub 2020 Nov 6.

Urology Department, Bichat-Claude Bernard Hospital, Assistance-Publique Hôpitaux de Paris, Paris University, Paris, France.

Background: Level 1 evidence supports the administration of single postoperative intravesical chemotherapy (pIVC) following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), in order to decrease intravesical recurrence risk.

Objective: The Young Academic Urologist Urothelial Cancer Group aimed to investigate the use of pIVC in daily practice among European colleagues.

Design Setting And Participants: An online survey was shared with European Association of Urology Section of Oncological Urology (ESOU) 2017 participants via e-mail. Submissions were accepted from April to June 2017. The topics for 15 questions of this survey included the habit of delivering pIVC, the choice of drug, its dosage, related doubts or concerns, reasons not to perform pIVC, knowledge of the evidence, and surgical preferences for RNU.

Outcome Measurements And Statistical Analysis: Survey software was used for analyses. Logistic regression analyses were used to investigate the association between surgeons' experience and caseloads with pIVC utilization.

Results And Limitations: Overall, 127 responses were collected (11.6%). About half of the participants (47%) regularly administered pIVC following RNU. The drug most commonly utilized was mitomycin (85%); 82% adhered to the standard dosage of 40 mg. Different administration protocols were adopted: ≤48 h (39%), 7-10 postoperative days (35%), >10 d (11%), and intraoperatively (10%). The evidence was supported by prospective randomized clinical trials for only 65% of responders. Among interviewees who did not deliver pIVC, the most commonly reported reasons were lack of supporting data (55%), fear of potential side effects (18%), and organizational hurdles (15%).

Conclusions: Our research highlights the limited use of pIVC following RNU for UTUC, raising the question of how the compliance with level 1 evidence in the urological community may be promoted.

Patient Summary: Level 1 evidence supports the administration of single postoperative intravesical chemotherapy (pIVC) following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), in order to decrease intravesical recurrence risk. The Young Academic Urologist Urothelial Cancer Group aimed to investigate the use of pIVC in daily practice among European colleagues. Our research highlights the limited use of pIVC (47%) following RNU for UTUC, raising the question of how the compliance with level 1 evidence in the urological community may be promoted.
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http://dx.doi.org/10.1016/j.euros.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317887PMC
December 2020

Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition.

Urol Oncol 2021 10 21;39(10):734.e11-734.e17. Epub 2021 Jul 21.

Decipher Urologic Cancers, Veracyte, Vancouver, British Columbia, Canada. Electronic address:

Purpose: Clinical high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC) represents a significant risk to patients, but these patients are not typically offered neoadjuvant therapies, including immune therapy. In this study, we determine whether patients with HG clinical T1 or T2 bladder urothelial carcinoma (UC) have profiles that predict the potential effectiveness of immune-checkpoint inhibitors (ICI).

Materials And Methods: Data from transurethral resection of bladder tumor (TURBT) specimens from 2 studies was evaluated. The molecular upstaging (MOL) cohort included HG cT1N0M0 (n = 87) and cT2N0M0 (n = 119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (n = 102) was used as ICI-treated reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher). Immune-signatures scores and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of recurrence-free survival (RFS) and overall survival (OS).

Results: In both the PURE-01 and MOL cohorts, the Immune190 signature, stratified by subtype, showed the highest scores in basal-type, but also in luminal-infiltrated tumors, but the lowest scores in the luminal tumors. However, in HG cT1 tumors the Immune190 scores were the lowest for luminal papillary tumors (Consensus, TCGA) and luminal tumors (GSC), with less distinct differences between other subtypes. RFS was significantly longer for luminal vs non-luminal tumors in MOL (P = 0.04) but not in PURE-01 (P = 0.8). In the MOL cohort, OS was inferior in HG cT1 tumors for Immune190-high vs low tumors (median split, P = 0.042).

Conclusion: We identified a population of cT1-T2N0M0 tumors in the MOL cohort that shared molecular features with tumors included in PURE-01. These profiles suggest that treatment with ICI could be proposed to more selected HG cT1N0M0 tumors, identified with a gene expression assay.
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http://dx.doi.org/10.1016/j.urolonc.2021.06.011DOI Listing
October 2021

Clinical Outcomes of Patients With Metastatic Urothelial Carcinoma After Progression to Immune Checkpoint Inhibitors: A Retrospective Analysis by the Meet-Uro Group (Meet-URO 1 Study).

Clin Med Insights Oncol 2021 8;15:11795549211021667. Epub 2021 Jul 8.

Vita Salute San Raffaele University and Department of Urology, IRCCS San Raffaele Hospital, Milano, Italy.

Background: Immune checkpoint inhibitors (ICIs) are currently the standard of care for metastatic urothelial cancer (mUC) after the failure of previous platinum-based chemotherapy. The choice of further therapy after ICI progression is a new challenge, and scarce data support it. We aimed to examine the outcomes of mUC patients after progression to ICI, especially when receiving chemotherapy.

Methods: Data were retrospectively collected from clinical records of mUC patients whose disease progressed to anti-programmed death 1 (PD-1)or programmed death ligand 1 (PD-L1) therapy at 14 Italian centers. Patients were grouped according to ICI therapy setting into SALVAGE (ie, ICI delivered ⩾ second-line therapy after platinum-based chemotherapy) and NAÏVE (ie, first-line therapy) groups. Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared among subgroups. Cox regression assessed the effect of treatments after progression to ICI on OS. Objective response rate (ORR) was calculated as the sum of partial and complete radiologic responses.

Results: The study population consisted of 201 mUC patients who progressed after ICI: 59 in the NAÏVE cohort and 142 in the SALVAGE cohort. Overall, 52 patients received chemotherapy after ICI progression (25.9%), 20 (9.9%) received ICI beyond progression, 115 (57.2%) received best supportive care only, and 14 (7.0%) received investigational drugs. Objective response rate to chemotherapy in the post-ICI setting was 23.1% (28.0% in the NAÏVE group and 18.5% in the SALVAGE group). Median PFS and OS to chemotherapy after ICI-PD was 5 months (95% confidence interval [CI]: 3-11) and 13 months (95% CI: 7-NA) for the NAÏVE group; 3 months (95% CI: 2-NA) and 9 months (95% CI: 6-NA) for the SALVAGE group, respectively. Overall survival from ICI initiation was 17 months for patients receiving chemotherapy (hazard ratio [HR] = 0.09, < 0.001), versus 8 months for patients receiving ICI beyond progression (HR = 0.13, < 0.001), and 2 months for patients who did not receive further active treatment ( < 0.001).

Conclusions: Chemotherapy administered after ICI progression for mUC patients is advisable irrespective of the treatment line.
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http://dx.doi.org/10.1177/11795549211021667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274126PMC
July 2021

Clinically Advanced Pheochromocytomas and Paragangliomas: A Comprehensive Genomic Profiling Study.

Cancers (Basel) 2021 Jul 1;13(13). Epub 2021 Jul 1.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Patients with clinically advanced paragangliomas (CA-Para) and pheochromocytomas (CA-Pheo) have limited surgical or systemic treatments. We used comprehensive genomic profiling (CGP) to compare genomic alterations (GA) in CA-Para and CA-Pheo to identify potential therapeutic targets. Eighty-three CA-Para and 45 CA-Pheo underwent hybrid-capture-based CGP using a targeted panel of 324 genes. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined. The GA/tumor frequencies were low for both tumor types (1.9 GA/tumor for CA-Para, 2.3 GA/tumor for CA-Pheo). The most frequent potentially targetable GA in CA-Para were in (7%, primarily amplifications), , , , and (all 2%) and for CA-Pheo in (9%, primarily fusions), (11%) and (7%). Germline mutations in known cancer predisposition genes were predicted in 13 (30%) of CA-Pheo and 38 (45%) of CA-Para cases, predominantly involving genes. Both CA-Para and CA-Para had low median TMB, low PD-L1 expression levels and none had MSI high status. While similar GA frequency is seen in both CA-Para and CA-Para, germline GA were seen more frequently in CA-Para. Low PD-L1 expression levels and no MSI high status argue against strong potential for novel immune checkpoint inhibitors. However, several important potential therapeutic targets in both CA-Para and CA-Para are identified using CGP.
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http://dx.doi.org/10.3390/cancers13133312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268679PMC
July 2021

The obesity paradox in metastatic castration-resistant prostate cancer.

Prostate Cancer Prostatic Dis 2021 Jul 5. Epub 2021 Jul 5.

Division of Hematology/Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Objective: To test whether body mass index (BMI) amongst patients with metastatic castration-resistant prostate cancer (mCRPC) is associated with overall survival (OS) and cancer-specific survival.

Methods: Individual patient data from 1577 men with mCRPC treated with docetaxel and prednisone from the control arms of ASCENT2, VENICE, and MAINSAIL were considered. The role of BMI on survival outcomes was investigated both as a continuous and categorical variable (≤24.9 vs. 25-29.9 vs. ≥30 km/m). BMI ≥ 30 kg/m was considered obese. Analyses were adjusted for age, PSA, ECOG performance status, number of metastases and prior treatment. The Cox semi-proportional hazard model was used to predict OS, whereas competing risks regression was used for predicting cancer-specific mortality (CSM). To exclude any possible effect attributable to higher doses of chemotherapy (titrated according to body-surface area), we checked for eventual interactions between BMI and chemotherapy dose (both as continuous-continuous and categorical-continuous interactions).

Results: The median (IQR) age for the patient population was 69 (63,74) years with a median (IQR) BMI of 28 (25-31) kg/m. Median follow-up for survivors was 12 months. Of the 1577 patients included, 655 were deceased by the end of the studies. Regarding OS, BMI emerged as a protective factor both as a continuous variable (HR: 0.96; 95% CI: 0.94, 0.99; p = 0.015) and as a categorical variable (obesity: HR: 0.71, 95% CI: 0.53, 0.96; p = 0.027, relatively to normal weight). The protective effect of high BMI on CSM was confirmed both as a continuous (SHR: 0.94; 95% CI: 0.91, 0.98; p = 0.002) and as a categorical variable (obesity SHR: 0.65; 95% CI: 0.45, 0.93; p = 0.018). No interaction was detected between the BMI categories and the docetaxel dose at any level in our analyses (all p » 0.05).

Conclusions: Obese patients with mCRPC had better cancer-specific and overall survival as compared to overweight and normal weight patients. The protective effect of BMI was not related to receiving higher chemotherapy doses. Further studies aimed at elucidating the biological mechanism behind this effect are warranted.
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http://dx.doi.org/10.1038/s41391-021-00418-0DOI Listing
July 2021

Comprehensive genomic profiling of histologic subtypes of urethral carcinomas.

Urol Oncol 2021 10 30;39(10):731.e1-731.e15. Epub 2021 Jun 30.

Foundation Medicine, Cambridge, MA.

Background: Carcinoma of the urethra (UrthCa) is an uncommon Genitourinary (GU) malignancy that can progress to advanced metastatic disease.

Methods: One hundred twenty-seven metastatic UrthCa underwent hybrid capture-based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden was determined on up to 1.1 Mbp of sequenced DNA, and microsatellite instability was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3).

Results: Forty-nine (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 24 (19%) adenocarcinomas NOS (UrthAC), and 12 (9%) clear cell (UrthCC) were evaluated. UrthUC and UrthSCC are more common in men; UrthAC and UrthCC are more common in women. Ages were similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; mTOR pathway GA in PTEN were also identified. GA in other potentially targetable genes were also identified including ERBB2 (6% in UrthUC, 3% in UrthSCC, and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC), and MET (8% in UrthCC). Possibly reflecting their higher GA/tumor status, potential for immunotherapy benefit associated with higher tumor mutational burden and PD-L1 staining levels were seen in UrthUC and UrthSCC compared to UrthAC and UrthCC. Microsatellite instability high status was absent throughout.

Conclusions: Comprehensive genomic profiling reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant, and metastatic disease trials.
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http://dx.doi.org/10.1016/j.urolonc.2020.12.021DOI Listing
October 2021
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