tbuckley/cabot-search huggingface dataset:
Association of prior poly(ADP-ribose) polymerase (PARP) inhibitor therapy with response to 177Lu-PSMA-617 (LuPSMA) in men with DNA damage repair (DDR) mutations.
Authors: Ruben Raychaudhuri, George Mo, Abuzar Moradi Tuchayi, Laura Graham, Roman Gulati, Colin C. Pritchard, Michael C. Haffner, Todd Yezefski, Jessica E. Hawley, Robert Bruce Montgomery, Heather H. Cheng, Peter Nelson, Delphine L Chen, Thomas A. Hope, Amir Iravani, Michael Thomas Schweizer
Journal: Journal of Clinical Oncology (2024)

128 Background: LuPSMA, a radioligand therapy targeting the cell surface protein PSMA, is approved for men with PSMA-positive mCRPC previously treated with androgen receptor signaling inhibitor (ARSI) and taxane chemotherapy. Several PARP inhibitors (PARPi) are also currently approved for patients with mCRPC harboring alterations in genes associated with DNA damage repair (DDR). Given that both therapeutics result in DNA damage, we hypothesized that there would be clinical evidence of cross-resistance between the two classes of agents, with decreased efficacy in patients receiving LuPSMA following a PARPi. Methods: We abstracted retrospective data from patients at three centers who received at least one cycle of LuPSMA per the FDA label and had panel-based tumor sequencing performed. Patients with PARPi qualifying mutations were included in the analysis. PSA 50 responses (i.e. ≥50% decline in PSA from baseline), PSA progression free survival (PFS) and overall survival (OS) following treatment with LuPSMA were compared between patients who received prior PARPi (PARPi-T cohort) and those who did not (PARPi-NT cohort). Results: Forty-nine patients with a PARPi qualifying alteration who received at least one cycle of LuPSMA were identified. Baseline characteristics (Gleason score, visceral metastases, race, ECOG PS, PSMA SUV mean/max ) were similar between cohorts. Prior non-PARPi lines of therapy, including receipt of radium-223 (14% vs 21%), carboplatin (33% vs 36%), ≥ 2 prior ARSI (67% vs 68%), and ≥ 2 prior taxanes (43% vs 47%) were also similar between the PARP-NT and PARP-T cohorts respectively. Median PSA PFS and OS were both significantly increased in the PARPi-NT cohort as compared to the PARPi-T cohort (Table). PSA 50 responses were numerically increased in the PARP-NT cohort, although this did not reach statistical significance. The most common PARPi qualifying alteration was BRCA2 (N=15). PARP-NT patients with BRCA2 alterations had significantly increased PSA PFS and OS as well as PSA 50 response rates compared to the PARP-T patients. Conclusions: Prior receipt of PARPi therapy appears to negatively associate with the clinical activity of LuPSMA, with the largest difference in outcomes observed in patients with BRCA2 mutations. These data support the hypothesis that PARPi therapy may lead to clinically significant cross-resistance with LuPSMA. Prospective studies to evaluate the optimal sequence of LuPSMA and PARPi therapy are justified. [Table: see text]
Borxpten: A phase II study of bortezomib (B) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with PTEN deletion.
Authors: Vinay Mathew Thomas, Colin Moynier, Kenneth M. Boucher, Blake Nordblad, Susan Clement, Michelle Esplin, Manish Kohli, Sumati Gupta, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami
Journal: Journal of Clinical Oncology (2024)

TPS258 Background: Despite recent therapeutic advancements, there is an unmet need for effective treatment options in mCRPC. The tumor suppressor gene PTEN maps to chromosome region 10q23 and is deleted in 30% of primary and 60% of castration-resistant prostate cancer. Approximately 40 kb upstream of PTEN is ATAD1, which encodes an ATPase involved in mitochondrial protein homeostasis on the outer mitochondrial membrane. ATAD1 is frequently co-deleted with PTEN, with the highest occurrence in prostate cancer (25%). Winter et al. demonstrated that cells harboring a Chr10q23 deletion highly depend on the ubiquitin-proteasome system and were exquisitely sensitive to the proteasome inhibitor, B (PMID: 36409067). Treatment of pts with mCRPC enriched for PTEN and ATAD1 co-deleted tumors with B could lead to an effective treatment approach in mCRPC. Herein we evaluate the efficacy of B in pts with mCRPC with PTEN deletion. Methods: This investigator-initiated, phase II, single-arm, single-center study will enroll 22 pts. Treatment: B will be administered at 1.3 mg/m 2 of the body-surface area subcutaneously on days 1, 4, 8, and 11 in a 21-day cycle. Key inclusion criteria: ≥18 years of age, mCRPC with histologically/cytologically confirmed adenocarcinoma without small cell histology, PTEN deletion on next generation sequencing, prior treatment with one androgen receptor pathway inhibitor (ARPI), no other treatment for mCRPC (except ARPI if not used in castration sensitive stage), ECOG performance status ≤ 2, adequate organ function. Key exclusion criteria: grade ≥ 2 neuropathy, untreated brain metastases or any spinal cord compression. Primary objective: To evaluate the antitumor activity of B in pts with mCRPC with PTEN deletion as assessed by PSA 30% response rate. Simon’s two-stage design will be used. The null hypothesis is that the true response rate is 20% which will be tested against a one-sided alternative. In the first stage, 10 pts will be accrued. If there are ≤2 responses, the study will be stopped. Otherwise, 12 additional pts will be accrued for a total of 22 pts. The null hypothesis will be rejected if ≥8 responses are observed in 22 pts. This design yields a type I error rate of 0.0492 and a power of 0.8065 when the true response rate is 45%. Secondary Objectives: 1) To assess the antitumor activity of bortezomib in pts with mCRPC with PTEN deletion as assessed by PSA 50% response rate, duration of PSA response, PSA progression free survival (PFS), objective response rate, duration of response, radiographic PFS, PFS, and OS 2.) To assess the safety and tolerability of B in pts with mCRPC with PTEN deletion. Exploratory analysis: Concurrent PTEN and ATAD1 loss will be correlated with treatment responses with B. Clinical trial information: NCT06029998 .
Assessing tobacco-related mortality trends in genitourinary cancers: A 1990-2019 analysis.
Authors: Chinmay Jani, Samuel A. Kareff, Ana S. Salazar, Janaki Neela Sharma
Journal: Journal of Clinical Oncology (2024)

368 Background: Tobacco consumption is a well-established risk factor for genitourinary cancers like urothelial and renal cell. This study aims to examine mortality trends associated with tobacco use in these cancer types, both globally and within the U.S., over the period of 1990 to 2019. Methods: Data from the Global Burden of Disease database, based on the International Classification of Diseases versions 10 and 9, were utilized to extract mortality statistics for bladder cancer (BC) and kidney cancer (KC). Age-standardized death rates (ASDRs) for the overall population, as well as Tobacco Attributable Mortality (TAM) were collected by sex and year. TAM was calculated by applying population attributable fraction to cause-specific deaths and disability-adjusted life years by year, location, age group and sex. The database also provided Annual Percentage Change (APC) data. Trends were analyzed using Joinpoint regression. Results: Smoking rates as well as mortality due to tobacco consumption have steadily decreased for both cancers in both sexes globally as well as in the U.S. during the study period. Globally, ASDRs exhibited a decreasing trend for BC and KC, and for both sexes, excluding an increase in ASDR for KC in males (+0.2). In the U.S. ASDR decreased for KC but not for BC in males (Table 1). BC demonstrated the highest proportion of tobacco-induced mortality among the three cancer types, with a nearly 50% contribution globally among males in 1990 that reduced to 39% in 2019. Overall, the tobacco-induced ASDR for kidney cancer in males remained relatively constant globally. Despite reductions over three decades, BC still exhibited a high proportion of mortality attributed to tobacco, particularly among males (39% globally; 31% in the U.S.). In 2019, the U.S. continued to experience higher tobacco-induced mortality rates among females for both KC (17.1 vs. 8.8%) and BC (26.9 vs. 14.3%) compared to the global average. Conclusions: Despite the multiple advances in cancer treatment in the last decades, TAM remains minimally unchanged. While there has been a general reduction in smoking rates overall, a substantial burden persists for tobacco-related malignancies—particularly for BC and KC. These findings underscore the need for heightened awareness and more robust tobacco control policies both globally and within the U.S. [Table: see text]
Criteria and indicators to evaluate quality of care in genitourinary tumor boards.
Authors: Javier Puente, Ferran Algaba Arrea, Oscar Buisán, Daniel Castellano, Ignacio Duran, Juan José Fernández Ávila, Alfonso Gómez-Iturriaga, Mariano Jose Parada Blázquez, Daniel Pérez Fentes, Gemma Sancho, Juan Antonio Vallejo Casas, Paula Gratal, Maria Teresa Pardo, Vicente Guillem
Journal: Journal of Clinical Oncology (2024)

388 Background: Multidisciplinary Tumor Boards are an essential component of patient management, as they integrate input from various healthcare professionals to make comprehensive decisions about patient care. Management of patients with genitourinary (GU) tumors particularly relies on these multidisciplinary Tumor Boards. However, there are no guidelines on how these groups should operate. Methods: A systematic literature review was conducted to identify criteria useful to evaluate quality in GU Tumor Boards (GUTB); publication dates were January 2016 to December 2021. A scientific committee—comprising 12 GU specialists from several disciplines—reviewed the literature findings, proposed a list of criteria, and developed and selected indicators using the Delphi method in a first round. Thirty-nine experts from various disciplines (urology, radiation oncology, radiology, medical oncology, nuclear medicine, hospital pharmacy, and pathology) participated in the second round of the Delphi method to evaluate the indicators. In both rounds the appropriateness and utility of the criteria and/or indicators were scored using a 9-point Likert scale (1, extremely inappropriate or not useful; 9, extremely appropriate or useful). Consensus was defined as at least two-thirds of Delphi respondents selecting a score sub-category (1–3, 4–6, or 7–9) that encompassed the median score of the group. Results: Forty-eight articles were selected from the literature review and were used to develop a list of 67 initial criteria. The scientific committee narrowed these criteria down to 45 to evaluate the quality of GUTB, covering five dimensions: organization (11 criteria), personnel (5 criteria), protocol and registry (21 criteria), resources (6 criteria), and interaction with patients (2 criteria). Then, 33 indicators were developed and evaluated in the first round of Delphi, which led to a selection of 26 indicators. In the second round the group of experts reached consensus on the appropriateness of all 26 indicators and on the utility of 24 of them. Finally, indicators were compiled into a list, including how they should be measured, so that they can be easily used in clinical practice. Conclusions: Criteria and indicators were developed by this working group to evaluate the quality of GUTB, aiming to serve as a guide to improve quality of care and achieve better outcomes in patients with GU.
Management, outcomes and predictors of recurrence in chromophobe renal cell carcinoma: Results from the Canadian Kidney Cancer information system (CKCis).
Authors: Erica Arenovich, Rodney H. Breau, Ranjeeta Mallick, Ricardo A. Rendon, Andrew Feifer, Frederic Pouliot, Simon Tanguay, Luke Lavallee, Jean-Baptiste Lattouf, Jasmir G. Nayak, Bimal Bhindi, Rahul K. Bansal, Antonio Finelli, Miles Mannas, Patrick O. Richard, Aly-Khan A. Lalani, Daniel Yick Chin Heng, Georg A. Bjarnason, Naveen S. Basappa, Lori Wood
Journal: Journal of Clinical Oncology (2024)

389 Background: Chromophobe RCC (chRCC) make up 5% of all RCC however data regarding baseline demographics, management, outcomes, and predictors of recurrence and survival is lacking. Methods: The Canadian Kidney Cancer Information System (CKCis) is a multi-institutional prospective cohort. Patients (pts) with clinically localized chRCC between Jan 2011-Aug 2023 were included. Descriptive statistics were used, time to recurrence and death were estimated using Kaplan-Meier estimates and associations were determined using Cox proportional hazards models. Results: chRCC made up 5.3% of all RCC pts in CKCis and only 2.4% presented with metastatic disease. This study cohort includes 797 pts who presented with localized disease. Median follow up 4.1 yrs, mean age 58.4 yrs and male in 58.5%. Management included: surgery 90.2%, surveillance 5.5%, or other local modalities 3.3%. Recurrence occurred in 59 pts (7.4%): 50 (85%) with metastases, 7 (12%) with local recurrence, and 2 (3.4%) with contralateral tumors. Median time to recurrence was 2 yrs. Management of recurrences included: systemic therapy in 46%, radiation in 29%, metastasectomy in 25%, surveillance in 8%. 5 and 10 year overall survival was 95% and 83% in all pts, 97% and 90% if no recurrence and 75% and 44% if recurrence. In the 90.2% (718 pts) treated with curative surgery, predictors of recurrence on multivariate analysis include: higher T stage, necrosis, and sarcomatoid features. Predictors of worse survival include: sarcomatoid features, larger tumor size, higher T stage, and higher number of comorbidities. Conclusions: In this large Canadian cohort, patients with chRCC usually present with localized disease and have relatively favorable oncologic outcomes, even when they recur. Larger tumors with sarcomatoid features have a worse survival and more intensive follow up may be beneficial. The favorable 5 and 10 year outcomes in chRCC are a reminder that studies must be conducted and reported for individual histologies and not as a large cohort of non clear cell RCC. [Table: see text]
Outcomes, frailty status, and body composition of men with hormone-sensitive prostate cancer treated with bicalutamide and dutasteride.
Authors: Justin M Lebenthal, Andrew Warren Hahn, Rebecca Tidwell, Krystal Zhang, Ana Aparicio
Journal: Journal of Clinical Oncology (2024)

122 Background: Prostate cancer is often a disease of the frail in which androgen withdrawal can further the risk of morbidity and mortality. This study aimed to describe a single institution experience with peripheral androgen blockade using bicalutamide and dutasteride (B+D) in men with hormone-sensitive prostate cancer (HSPC) in the context of body composition and frailty. Methods: Patients with HSPC treated with B+D at MD Anderson Cancer Center between 2010 and 2022 were retrospectively identified. Baseline and post-B+D frailty scores were calculated using the G8 geriatric score. Body composition was objectively measured from pre-treatment CT imaging. Differences in patient and disease characteristics between frail vs. not frail patients were compared with Kruskal Wallis tests or chi-square tests. Time on treatment (ToT), time to next treatment (TTnT) and overall survival (OS) were calculated by Kaplan-Meier methods, and comparisons by frailty status were made with the log rank test. Results: Forty-four patients were evaluable: median G8 frailty score was 13.5 with 22 patients classified as frail (G8 score ≤ 14) at baseline and after 6 months of B+D. ToT was shorter in frail individuals than non-frail (18.9 vs 38.2 months, p=0.03). TTNT was also shorter in frail individuals (20.9 vs 38.2 months, p=0.03). Only 3 patients have died, and 5-year OS is 81.3% for the entire cohort. Sarcopenia was found in 11 patients (52%) and sarcopenic obesity in 3 (14%). Conclusions: Bicalutamide and dutasteride was generally safe and feasible in a cohort of HSPC with increased pre-treatment frailty and sarcopenia. These findings suggest that peripheral androgen blockade is a eugonad treatment option that may warrant prospective study in at-risk populations and the application of frailty scores and measures of body composition can refine the relevant population. [Table: see text]
Outcomes after primary retroperitoneal lymph node dissection in men with stage 2 non-seminomatous germ cell tumour: A multicenter retrospective cohort study.
Authors: Luca Antonelli, Axel Heidenreich, Aditya Bagrodia, Nicolas Branger, Timothy Clinton, Siamak Daneshmand, Hooman Djaladat, Robert James Hamilton, Matthew Ho, Wade J. Sexton, David Nicol, Nicola Nicolai, Kathleen Olson, James Porter, Nirmish Singla, Sean P. Stroup, Angelika Terbuch, Clint Cary, Christian Daniel Fankhauser
Journal: Journal of Clinical Oncology (2024)

516 Background: Based on only smaller retrospective cohort studies, current guidelines recommend primary retroperitoneal lymph node dissection (RPLND) for men with marker-negative stage 2a non-seminomatous germ cell tumor (NSGCT). We aimed to reassess the role of primary RPLND in marker negative stage 2a, explore results in stages 2b/c and/or marker-positive disease, and evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Methods: Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for stage 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and progression-free survival (PFS). Results: A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.09, p-value = 0.02), but it did not correlate with PFS. The 5-year PFS rates were 85% for men with pure teratoma, 94% for men with viable cancer who received adjuvant chemotherapy, and 72% for men with viable cancer who did not receive adjuvant chemotherapy. The number of adjuvant chemotherapy cycles did not significantly affect PFS. Conclusions: Our study suggests considering primary RPLND not only in marker negative clinical stage 2a but also marker negative clinical stage 2b. Further research should identify the efficacy in men in other stages (2C or marker positive) and which patients may benefit from adjuvant chemotherapy and the optimal cycle number.
Association of initial adjustment dose of apalutamide with progression to castration-resistant prostate cancer and skin-adverse events in men with metastatic castration-sensitive prostate cancer: A multicenter retrospective study of CsJUC cohort.
Authors: Yoichiro Tohi, Takuma Kato, Keita Kobayashi, Kei Daizumoto, Hideo Fukuhara, Shin Ohira, Satoshi Katayama, Ryutaro Shimizu, Atsushi Takamoto, Kenichi Nishimura, Kenichiro Ikeda, Taichi Nagami, Mikio Sugimoto
Journal: Journal of Clinical Oncology (2024)

137 Background: Japanese patients with prostate cancer (PC) treated with apalutamide often encounter skin-adverse events (AE), which might lead to adjust the initial-dose of apalutamide. However, concerns have emerged regarding the potential impact of these dose adjustments on the overall efficacy of apalutamide in real-world clinical practice. We aimed to evaluate the association between adjustment of apalutamide dose and clinical outcome in Japanese men with metastatic castration-sensitive PC (mCSPC). Methods: We retrospectively evaluated 108 mCSPC patients treated with apalutamide. We divided patients into two groups: initial full-dose and reduced-dose recipients. The primary outcome was the impact of apalutamide dose adjustment on progression to castration-resistant prostate cancer (CRPC) and PSA response. The secondary outcomes were the impact of apalutamide dose adjustment on the incidence of the skin-AE. Results: Initial reduced-dose recipients of apalutamide were observed in 16.7%. There were no differences in cancer characteristics, such as CHAARTED criteria between the groups. Initial full-dose recipients were significantly associated with a longer time to CRPC than initial reduced-dose recipients [median NA (NA - NA) vs. 19 months (95% CI, 10 - NA), P=0.0161], although the percentages of the initial full-dose recipients who reduced apalutamide dose were 30%, 44.4%, 60%, and 63.3% at 3, 6, 9, and 12 months, respectively. The percentage of PSA &lt;0.2 decline at 3 months did not differ between the groups (59.1% vs 50%, P=0.602), but overall PSA 90% decline was higher in the initial full-dose recipients (88.8% vs 66.7%, P=0.027). Skin-AE occurred 50% in initial reduced-dose recipients and 51.1% in initial full-dose recipients, with no difference between the groups (P&gt;0.999). Furthermore, time to skin-AE was not different between the groups (74 days vs. 69 days, P=0.992). Conclusions: Our study suggested the potential negative implications of initial apalutamide dose adjustments on clinical outcomes in Japanese men with mCSPC.
Measuring oncological value of exercise and statin: Can we improve the prognosis of patients with cancer and change the microenvironment in different tumor types with exercise and statins (MOVES study)?
Authors: Jorma T.J Sormunen, Annastiina Hakulinen, Jukka Kemppainen, Leena Tiainen, Synnöve Staff, Krista Kankaanranta, Teemu Murtola
Journal: Journal of Clinical Oncology (2024)

TPS234 Background: Hypoxia is an important mechanism in cancer cells, which protects them from body’s immune reactions. Exercise improves circulation thus reducing hypoxia. Therefore, we study the effect of exercise and statins on prognosis of cancer patients. Lipid metabolism is an important energy source during hypoxia. We expect to see that patients who participate in regular physical exercise and use lipid-lowering medicine atorvastatin have longer survival than patients without such intervention. Methods: The MOVES study is an open-label single-centre randomised controlled phase 3 pilot trial. A total of 240 adult patients with stage IV cancer (prostate, renal cell, breast or ovarian) and starting 1 st line oncological treatment are randomised 1:1:1 into one of three groups: 1) Supervised exercise for 3 months; 2) Supervised exercise with 40 mg atorvastatin daily for 3 months; and 3) Control group. Patients are followed at 3-month intervals for up to two years. Choice of oncological treatment is up to the clinician’s discretion according to the patient’s clinical need. Radiological, clinical and/or biochemical progression, death, side effects of the treatments and interruptions of the cancer treatments are registered. The primary outcome is progression-free survival, measured as time to 2 nd line oncological treatment or death. The secondary outcomes are overall survival, quality of life, levels of hypoxia markers and cancer metabolites in blood and urine and treatment tolerability. A substudy will implement EF5-PET and FDG-PET scans to evaluate tumor hypoxia and metabolic activity before and after the trial intervention. The Ethics Committee of Tampere University Hospital has approved the study protocol. Results will be published after completion of the study in international peer viewed journals. Clinical trial information: NCT05796973 .