bluuebunny/crossref_metadata_2025 huggingface dataset:
Need for organ preservation in postchemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Nestler Tim , Paffenholz Pia , Pfister David , Maatoug Yasmine , Che Yue , Hiester Andreas , Albers Peter , Heidenreich Axel
Published: June 2022

5031

Background: The aim ofPC-RPLND for advanced nonseminomatous germ cell tumors is to resect all remaining metastatic tissue. So far, the resection of adjacent visceral or vascular organs is also commonly performed to achieve complete resection of the residual mass. To determine the possibility of more organ preservation, we aimed to analyze the pathohistology of patients with adjunctive surgery as the frequency of metastatic involvement in those organs with teratoma or vital cancer is currently unknown. Methods: We reviewed a cohort of 1204 patients who underwent PC-RPLND between 2008 and 2021 as a 2-center study and identified 242 (20.1%) cases of adjunctive surgery during PC-RPLND. We analysed the pathohistological presence of germ cell tumor elements in the resected organs: viable tumor (V), teratoma (T) or necrosis / fibrosis (N). Surgery associated complications were reported according to the Clavien-Dindo classification. Outcomes of subgroups were compared by using log-rank test. Results: V, T and N were present in 54 (22%), 94 (39%) and 94 (39%) of all patients with adjunct resected organs. In 242 patients, 325 adjunct organs were resected with 66 (27.3%) of these patients receiving a resection of multiple organs. The kidney was the most often resected organ (n = 77; V: 29% T: 39% N: 32%), followed by V. Cava (n = 67; V: 25% T: 36%, N: 39%) and partial liver resections (n = 50; V: 16%, T: 30%, N: 54%). Postoperative complications occurred in 30% of which 22% were Clavien grade III-V, showing no significant differences between V, T and N; p = 0.093. 27% of all patients suffered from a relapse during a median follow-up of 22 months [0-180]. Patients with T or V in the resected specimens had a significantly reduced 5-year RFS compared to patients with only N (39%, 81%, p < 0.001). Conclusions: This study shows tremendous need for more organ preservation as 40% of all resections of adjunct organs are oncologically unnecessary due to the presence of N only in the pathological specimens. Therefore, in case of doubt, we should increase intraoperative frozen section to avoid oncologically unnecessary adjunctive surgeries, especially nephrectomies and vascular resections. Additionally, serological or image-based means for a more accurate presurgical workup are required to spare patients with N from PC-RPLND in general.
Epigenetic age acceleration in U.S. testicular cancer survivors (TCS).
Authors: Zheng Yinan , Wang Jun , Dinh Paul C. , Nathanson Katherine L. , Weathers Benita , Jacobs Linda A. , Vaughn David J. , Hou Lifang , Travis Lois B.
Published: June 2022

5033

Background: Given the young age at diagnosis and effective therapies (cisplatin-based chemotherapy and/or surgical approaches), most TCS gain many decades of life. Attention has been drawn to the potential downsides of these treatment successes, including the accelerated development of age-related diseases. Previous studies have suggested that cytotoxic treatment and carcinogenesis are associated with epigenetic changes, leading to premature biological aging processes. Methods: We recruited 24 TCS managed with surgical approaches alone and 24 cisplatin-treated TCS (all also treated with surgical removal of the cancerous testis) and who had histologic/serological germ cell tumor diagnosis before 55 years, and were disease-free at routine follow up. We also included 310 cancer-free race- and age-matched (+/- 5 years) males from a normative cohort, i.e., the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We undertook genome-wide interrogation of blood DNA methylation (DNAm) using the Illumina Infinium Methylation EPIC BeadChip (EPIC array). We quantified aging using DNAm GrimAge, a validated, composite biomarker consisting of DNAm surrogate biomarkers of seven plasma proteins associated with various age-related conditions plus a DNAm surrogate of smoking pack-years. The comparison analysis was adjusted for age, race, smoking status, blood cell type proportions estimated using DNA methylation batch effect, and other laboratory-related technical factors. Results: The median chronological age of TCS was 28 years (range 19-64) with 25% smokers. Compared to their chronological age, TCS managed with surgical approaches alone had a mean GrimAge of 39.4 years (i.e., 9.2 years older, paired t-test P = 0.001), and cisplatin-treated TCS had a mean GrimAge of 45.2 years (i.e., 14.9 years older, paired t-test P < 0.001). Compared to the matched CARDIA controls, TCS managed with surgical approaches alone were on average 3.0 years epigenetically older (P = 0.093), and cisplatin-treated TCS were on average 11.2 years epigenetically older (P < 0.001), suggesting an increasing trend with treatment burden (P-trend < 0.001). Conclusions: Our data showed a faster epigenetic aging process in TCS. Consistent with previous studies, our data is in line with the hypothesis that TC cytotoxic treatment may induce premature aging. Although TCS managed with surgical approaches alone had no exposure to cytotoxic drugs, their epigenetic age may also be accelerated due to TC development and/or risk factors that contributed to it as well as post-therapy factors.
Impact of activating androgen receptor (AR) mutations on AR sensitivity to alternative ligands and response to ODM-208, a selective, first-in-class CYP11A1 inhibitor, in patients with advanced metastatic castration-resistant prostate cancer (mCRPC).
Authors: Bernard-Tessier Alice , Utriainen Tapio , Cook Natalie , Barthélémy Philippe , Lallous Nada , Gleave Martin , Ikonen Tarja , Riikonen Reetta , Pohjanjousi Pasi , Garratt Chris , Fizazi Karim
Published: June 2022

5057

Background: Activating AR mutations ensure a continued AR activation by non-androgen steroid ligands, e.g. progesterone and glucocorticoids. CYP11A1 is the only enzyme that catalyzes the conversion of cholesterol to pregnenolone, from which all steroid hormones (glucocorticoids, mineralocorticoids, and sex steroids) are subsequently derived. ODM-208, an oral, selective inhibitor of CYP11A1, is being evaluated for safety and efficacy as a treatment of mCRPC in the ongoing CYPIDES phase I/II trial in men previously treated with both novel hormonal therapies and taxanes (ClinicalTrials.gov identifier: NCT03436485). Preliminary phase 1 results were previously reported (Fizazi K et al., ASCO GU 2022). Here we confirm that the in-vitro sensitivity of common AR mutations to ODM-208 treatment is mirrored in patient response in CYPIDES phase 1. Methods: ODM-208 was administered at daily doses between 6-150 mg (phase 2 dose: 10 mg) with dexamethasone and fludrocortisone, resulting in maximal suppression in all measured steroids at all doses. AR ligand-binding domain (LBD) mutations (L702H, V716M, W742L, W742C, H875Y, F877L, T878A, T878S, M896T, M896V) were assessed using a BEAMing assay (Sysmex Inostics) from plasma circulating cell-free DNA (cfDNA) collected before the first dose of ODM-208. The activation of wild-type (wt) and LBD mutated AR with various ligands was also studied in vitro using a luciferase reporter assay in AR negative PC3 cells. Results: 17 of 44 patients had at least one AR activating mutation, the most frequent being L702H (n = 11), T878A (n = 10), and H875Y (n = 6). Eleven out of the 16 evaluable patients (68%) with an AR LBD mutation achieved ≥50% reduction in serum PSA compared with 2 out of the 24 evaluable patients (8%) without an AR LBD mutation (P <.0001). The in vitro sensitivity of each of these common AR mutations to a variety of non-androgenic steroids will be presented, along with detailed PSA responses, duration of responses, and safety in mCRPC patients bearing the same mutations. Conclusions: AR activating mutations may permit continued hormone dependence in mCRPC, related to actions of non-androgenic steroid hormones. Treatment with ODM-208 blocked all steroid hormone production and resulted in frequent ≥50% PSA reductions in this group of heavily pretreated mCRPC pts with various AR LBD mutations, some being long-lasting. cfDNA AR mutations are a promising predictive biomarker for ODM-208 efficacy. Dexamethasone did not activate mutated ARs, supporting its selection for glucocorticoid replacement therapy in combination with ODM-208. Clinical trial information: NCT03436485.
Radiographic progression in the absence of prostate-specific antigen (PSA) progression in patients with metastatic hormone-sensitive prostate cancer (mHSPC): Post hoc analysis of ARCHES.
Authors: Armstrong Andrew J. , Mottet Nicolas , Iguchi Taro , Szmulewitz Russell Zelig , Holzbeierlein Jeffrey , Villers Arnauld , Alcaraz Antonio , Alekseev Boris , Shore Neal D. , Gomez-Veiga Francisco , Rosbrook Brad , Zohren Fabian , Lee Ho-Jin , Haas Gabriel P. , Stenzl Arnulf , Azad Arun
Published: June 2022

5072

Background: Enzalutamide (ENZA) + androgen deprivation therapy (ADT) significantly reduced the risk of radiographic progression and increased overall survival in men with mHSPC, regardless of baseline PSA levels (ARCHES; NCT02677896). This post hoc analysis investigated concordance between PSA progression and radiographic progression in patients with mHSPC. Methods: Patients with mHSPC (n=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT or placebo (PBO) + ADT. The concordance between radiographic progression and PSA progression, as defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria, and between any rise in PSA above nadir was assessed. Results: In total, 267/1150 patients in ARCHES had radiographic progression (ENZA + ADT, n=79; PBO + ADT, n=188). At radiographic progression, the median (range) PSA for ENZA + ADT-treated patients was 2.25 ng/mL (0–1062.3 ng/mL) and 17.47 ng/mL (0–1779.5 ng/mL) for PBO + ADT-treated patients. Most patients (67%) treated with ENZA + ADT did not have PCWG2-defined PSA progression at radiographic progression, compared with 43% of those treated with PBO + ADT (Table). The median absolute and percentage rise in PSA from nadir to radiographic progression was 0.77 ng/mL and 200%, respectively, with ENZA + ADT compared with 12.23 ng/mL and 367%, respectively, with PBO + ADT. Conclusions: In this post hoc analysis of ARCHES, we found frequent discordance between radiographic progression and PSA progression by PCWG2 criteria or any PSA rise over nadir in patients with mHSPC treated with ENZA + ADT. Thus, regular imaging is recommended to detect radiographic progression among patients treated with potent androgen receptor pathway inhibitors, such as ENZA + ADT, as serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients. Clinical trial information: NCT02677896. [Table: see text]
Physician perspectives on extrapolating data from trials testing less-intense treatment to underrepresented populations.
Authors: Rocque Gabrielle Betty , Andrews Courtney J. , Lawhon Valerie , Ingram Stacey A. , Frazier Rachel Marie , Smith Mary Lou , Wagner Lynne I. , Zubkoff Lisa , Wallner Lauren P. , Wolff Antonio C.
Published: June 2022

521

Background: Clinical trials provide the foundation for evidence-based practices, yet trial participants are often not representative of all patients. Historically, clinical trials involved adding novel agents to standard of care to improve survival. There has been a shift to an individualized approach with testing less intense treatment, yet vulnerable patient groups are at risk for underrepresentation. Little is known about physician perspectives on implementing less intense treatment approaches for patients who are not represented in sufficient number to draw conclusions on subpopulations. Methods: Open-ended, individual qualitative interviews with medical oncologists from different cancer centers exploring their perspectives on trials that test less intense treatment for patients with cancer. Interviews were audio-recorded and transcribed. Four independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. Results: Of the 39 participating physicians, 61.5% felt comfortable extrapolating, 30.8% were hesitant, and 7.7% would not feel comfortable extrapolating trial outcomes to underrepresented populations. One physician noted, “We've been extrapolating for as long as I can remember and certainly that I've been in practice; so we do need to do better there, but extrapolation is only natural with what we have.” Facilitators of comfort included sentiment that “biology is biology”, such that the cancer characteristics were what mattered; the strength of the evidence from the trial overall; inclusion of subset analysis on underrepresented populations; and prior experience making decisions with limited data. Barriers to extrapolation included the potential harm over the patient’s lifetime; concerns about groups that had minimal participants; application specifically to younger patients; and extending findings to racially and ethnically diverse populations. Oncologists highlighted the need for shared decision-making when applying study results to underrepresented populations. They also expressed concerns about study findings being applied to patients who would have been ineligible in the original trials. Universally, broader inclusion in trials testing lowering chemotherapy is desired. Conclusions: The majority (92%) of physicians report that they would extrapolate clinical trial results to patients poorly represented in de-escalation trials, while expressing concerns about applicability to specific subpopulations based on tumor characteristics (e.g. stage, biology) and patient demographics (e.g. age, race). Further work is needed to increase clinical trial representation of diverse populations to safely and effectively optimize treatment for patients with cancer.
Association of progesterone receptor status with 21-gene recurrence score and survival among patients with estrogen receptor-positive breast cancer.
Authors: Ma Sung Jun , Gill Jasmin , Yendamuri Keerti , Yu Brian , Yao Song , Oladeru Oluwadamilola Temilade , Singh Anurag K.
Published: June 2022

529

Background: Among patients with estrogen receptor (ER)-positive breast cancer, progesterone receptor (PR)-negative tumors were shown to have worse prognosis than PR-positive tumors. However, PR-negative tumors were underrepresented in trials such as TAILORx and RxPONDER, and the role of PR status in the setting of 21-gene recurrence score (RS) remains unclear. We performed an observational cohort study to evaluate the association of PR status with RS and the magnitude of chemotherapy benefits on survival. Methods: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, pT1-3N0-1a breast cancer who underwent surgery and endocrine therapy. Logistic and Cox multivariable analyses (MVA) were used to identify variables associated with high RS (> 25) and overall survival (OS), respectively. Interaction test was performed among PR status, chemotherapy, and nodal staging. Propensity score matching was performed to reduce selection bias. Sensitivity analysis was performed after excluding those with postdiagnosis survival of less than 6 months to reduce immortal time bias. Results: A total of 143,828 patients met our criteria (n = 110,421 for PR-positive/pN0, n = 11,897 for PR-negative/pN0, n = 19,928 for PR-positive/pN1a, n = 1,582 for PR-negative/pN1a). Median follow up was 51.5 months (interquartile range 34.8-71.9). On logistic MVA, PR-negative tumors were more likely to have high RS (adjusted odds ratio [aOR] 6.68, 95% confidence interval [CI] 6.40-6.97, p < 0.001). On Cox MVA, PR-negative tumors were associated with worse OS (adjusted hazards ratio [aHR] 1.20, 95% CI 1.10-1.31, p < 0.001). Interaction among PR status, chemotherapy, and nodal staging was statistically significant (interaction p = 0.049). On subgroup analyses, the magnitude of chemotherapy benefit for OS was comparable among pN0 tumors (PR-positive: aHR 0.74, 95% CI 0.66-0.82; PR-negative: aHR 0.63, 95% CI 0.51-0.77) and was greater for PR-negative status among pN1a tumors (PR-positive: aHR 0.57, 95% CI 0.47-0.67; PR-negative: aHR 0.31, 95% CI 0.20-0.47). Similar findings were noted in 9,979, 1,822, 4,196, and 354 matched pairs for PR-positive/pN0 (HR 0.43, 95% CI 0.37-0.50), PR-negative/pN0 (HR 0.53, 95% CI 0.41-0.69), PR-positive/pN1a (HR 0.55, 95% CI 0.45-0.67), and PR-negative/pN1a (HR 0.25, 95% CI 0.14-0.45) tumors, respectively. On sensitivity analysis, our findings were consistent in Cox MVA using interaction and subgroup analyses. Conclusions: To our knowledge, this is the largest study using a nationwide oncology database suggesting that PR-negative status is an independent, adverse prognostic factor for survival associated with high RS, with greater chemotherapy benefits compared to PR-positive status among pN1a tumors even after adjusting for RS.
A prognostic model for distant recurrence-free survival in triple-negative breast cancer (TNBC) and the outcomes of initiation of adjuvant chemotherapy in the risk of relapse.
Authors: Morante Zaida , Ferreyra Yomali , Pinto Joseph , Valencia Guillermo , RiojaViera Patricia Elizabeth , Fuentes Hugo , Neciosup Silvia P. , Cotrina José M. , Gomez Henry Leonidas
Published: June 2022

530

Background: TNBC is a highly complex, heterogenous disease associated with poor outcomes, high incidence of distant metastases, and limited treatment options. With the purpose of identify patients at different risk of distant recurrence, we developed a prognostic model using clinicopathological characteristics that contribute to the risk of recurrence in TNBC patients and also evaluate its influence in the time of beginning of adjuvant therapy. Methods: We retrospectively analyzed 687 TNBC patients who received adjuvant chemotherapy between January 2000 to December 2014 at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru). The database was randomly divided into two groups to create a discovery set (n = 344) and a validation set (n = 343). Univariate and multivariate Cox regression analysis was conducted to identify prognostic factors for distant recurrence-free survival (DRFS). We developed a linear risk score based on clinicopathologic characteristics. Under STEPP methodology we classified patients at high, intermediate or low-risk of distant recurrence and the absolute treatment effects of time to initiation of chemotherapy (TTC, ≤ 30 vs > 30 days) through risk subgroups was estimated. Results: The median of follow-up was 9.90 years. In total, 31.0% (n = 213/687) relapses were registered. Variables associated with DRFS in the multivariate analysis were: age, T-staging, and N-staging. A tumor staging of T3-T4 vs. T1/T2 (HR = 2.92, 95%CI: 1.39 - 6.17), followed by the number of positive lymph nodes (N2-N3 vs N0/N1; HR = 2.78, 95%CI: 1.74 - 4.45) and an older age (≥ 60 years vs. ≤ 40/41-59, HR = 2.66, 95%CI: 1.46 - 4.88) were the clinicopathologic characteristics contributing to a higher risk score according to the 3-variable model. Also, 3 risk groups were identified and corroborated in the validation group. In the discovery set, patients with a TTC > 30 days experienced an overall decreased of 17.5% (95%CI: 6.7 - 28.3) in 10-year DFRS vs. those who initiated adjuvant therapy before 30 days. The impact of TTC > 30 days was higher in patients classified as high-risk (Decreased 10-year DFRS: 53.3 ± 28.8 %), similar findings were found in the validation set. Conclusions: A prognostic model based in clinicopathological characteristics (age, pT and pN), was able to classify TNBC patients’ candidates to adjuvant chemotherapy in 3 prognostics groups. We identified a subgroup of patients in which delaying of adjuvant chemotherapy (> 30 days) confers very high-risk of relapse.
Ovarian function suppression is not indispensable in patients with early breast cancer who are older than age 40.
Authors: Xian Jianqiao , Zhang Kaiming , Sun Ya , Wang Yan , Xie Xinhua , Ye Feng , Li Xing , Yin Jun , Wei Weidong , Xiao Xiangsheng , Xie Xiaoming , Wang Xi , Tang Jun
Published: June 2022

539

Background: Based on SOFT/TEXT studies, ovarian function suppression (OFS) has become the standard treatment for pre-menopausal breast cancer patients. However, a few studies reported more than 80% pre-menopausal breast cancer patients over 40 years old experienced permanent chemotherapy-induced amenorrhea (CIA) after chemotherapy, suggesting that these patients may not benefit from OFS. The purpose of this study was to evaluate the application value of OFS in early pre-menopausal hormonal receptor (HR)-positive breast cancer patients who experienced chemotherapy after 40 years old. Methods: 1386 pre-menopausal patients over 40 years of age with early HR-positive breast cancer underwent chemotherapy from 2010 to 2017 at the Sun Yat-Sen University Cancer Center. Serum hormone levels were used to define pre-menopausal status. OFS only referred to gonadotropin-releasing hormone agonist (GnRHa). Propensity score matching (PSM) was performed to reduce the selection bias between patients administrated with OFS and those without OFS. The prognostic value of OFS was determined using Kaplan-Meier and Cox proportional hazards analysis. Results: A total of 1386 patients (median age, 46 years; rang, 40-55 years) were enrolled in this study, 258 patients were treated with OFS and 1128 patients did not receive OFS treatment. After PSM, there were 258 patients allocated in Non-OFS group and 258 patients in OFS group. There had no statistically significant difference in terms of overall survival (OS) (p=0.5) and disease-free survival (DFS) (p=0.62) between Non-OFS group and OFS group. In Non-OFS group, 100 patients (8.86%) resumed menstruation after chemotherapy, and 1028 patients (91.14%) experienced permanent CIA. There also had no statistically significant difference in either OS (p=0.35) or DFS (p=0.79) between menstrual recovery group and permanent CIA group. In terms of the menstrual recovery duration time of the 100 patients who resumed menstruation, 37 patients (37%) were ≤ 6 months, 18 patients (18%) were 7 ̃ 12 months, and 45 patients (45%) were ＞ 12 months. In terms of the intervals from last time of chemotherapy to the beginning of menstrual recovery, 29 patients (29%) were ≤ 6 months, 16 patients (16%) were 7 ̃ 12 months, and 55 patients (55%) were ＞ 12 months. Finally, we analyzed the survival difference of different menstrual recovery durations and different intervals. We found that there still had no statistically significant difference in different recovery durations (OS, p=0.15; DFS, p=0.19) and different intervals (OS, p=0.11; DFS, p=0.24). Conclusions: In this study, early pre-menopausal HR-positive breast cancer patients who experienced chemotherapy after 40 years old did not benefit from OFS treatment in DFS and OS. These results suggest that OFS is not indispensable in early HR-positive breast cancer patients aged over 40 years.
Adjuvant chemotherapy is associated with an overall survival benefit regardless of age in patients with ER+/HER2-breast cancer with 1-3 positive nodes and Oncotype DX recurrence score 20 to 25: A National Cancer Database analysis.
Authors: Cao Lifen , Towe Christopher W. , Luo Xun , Stabellini Nickolas , Amin Amanda L. , Montero Alberto J.
Published: June 2022

540

Background: Based on the results of the RxPonder trial, post-menopausal women over age 50 with estrogen receptor (ER)+ breast cancer, 1-3+ nodes, and a 21-gene Oncotype DX recurrence score (RS) score of <25, did not benefit from receiving adjuvant chemotherapy. By contrast, adjuvant chemotherapy was beneficial in premenopausal women. We aimed to replicate the RxPonder trial using a larger sample sizes with real world data to determine whether a threshold with RS exists where adjuvant chemoendocrine therapy (CET) is beneficial regardless of age. Methods: The National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS <25 who received endocrine therapy (ET) only or CET. Interaction was explored between CET and age as a surrogate for menopausal status in the Cox regression models. Results: The final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS >20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age < = 50: HR = 0.334, P = 0.002; age > 50: HR = 0.521, P = 0.019). Conclusions: Among women with ER+/HER2- breast cancer with 1–3 positive nodes, and RS of 20-25, in contrast to the RxPonder trial we observed that CET was associated with an OS benefit in women regardless of age.
Clinical utility of genomic recurrence risk stratification in early, hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer.
Authors: Choucair Khalil , Page Seth Joel , Mattar Bassam Ibrahim , Dakhil Christopher , Nabbout Nassim H. , Deutsch Jeremy Michael , Truong Quoc Van , Truong Phu Van , Moore Dennis Frederic , Cannon Michael W. , Kallail K. James , Moore Joseph A , Dakhil Shaker R. , Diab Radwan , Kamran Syed , Reddy Pavan S.
Published: June 2022

546

Background: RNA-based genomic assessment of recurrence risk is used to estimate chemotherapy benefit in patients with hormone-receptor positive (HR+)/Human Epidermal Growth Factor 2-negative ( ERBB2-) breast cancer (BC). While originally validated in patients who met established clinicopathologic guidelines for consideration of adjuvant chemotherapy, it is virtually used in all patients with early HR+/ ERBB2- BC regardless of clinical recurrence risk. Methods: We conducted a retrospective chart review of adult patients with early-stage (T1-3; N0; M0) HR+/ ERBB2- BC who underwent genomic risk assessment of recurrence using the Oncotype DX (Exact Sciences) 21-genes assay, between January 2015 and December 2020. Clinicopathologic features were collected to assess the clinical recurrence risk. A low clinical risk score (CRS) was defined as a tumor size ≤ 3 cm in diameter with histologic grade 1, or ≤ 2 cm with grade 2 or ≤ 1 cm with grade 3. A composite risk score of distant recurrent (RRS), derived from a COX model using data from the SOFT and TEXT trials ( https://rconnect.dfci.harvard.edu/CompositeRiskSTEPP/ ), was also computed for 374 patients for whom clinical data was available. RRS > 1.42 was defined as high. High genomic risk of recurrence was defined as a score (GRS) ≥25. The data was collected under IRB approval. Results: A total of 517 patients with early-stage disease were referred for genomic testing, and clinical data was available for 501 of them. Median age was 69 years (IQR=13), median tumor size 1.03 cm (IQR=0.9), and grade 2 histology (57.49%) was the most common. Results of recurrence risk, using the 3 prognostication methods, are summarized in Table. Within patients with low CRS (n=349), 9.17% had a high GRS, compared to 8.93% in patients with low RRS (n=280). In patients with grade 1 histology (n=130), 3.85% had a high GRS and 68.46% had tumors > 1cm, of whom only 4.49% had a high GRS. Tumor size > 1cm did not associate with a high GRS (Fisher’s Exact test; P=1.00). Conclusions: In patients with early HR+/ ERBB2- BC, <10% of patients with low clinical risk, and <5% of patients with grade 1 tumors, had a high genomic recurrence risk, respectively. Given current NCCN recommendation for testing, our findings raise the question of whether genomic testing for patients with grade 1 tumors can be safely omitted, irrespective of size, and call for a better understanding of the need for routine genomic testing in patients with low grade/low clinical risk of recurrence. [Table: see text]
Establishment of a novel BRCAness score that predicts response to PARP inhibitors.
Authors: Oshi Masanori , Gandhi Shipra , Wu Rongrong , Asaoka Mariko , Yan Li , Yamada Akimitsu , Narui Kazutaka , Yamamoto Shinya , Ishikawa Takashi , Endo Itaru , Takabe Kazuaki
Published: June 2022

549

Background: BRCAness is a generic term used to describe characteristic features of homologous recombination deficiency (HRD) mimicking mutations in BRCA genes. Although clinical genetic testing has increased the detection of mutations in BRCA1 and BRCA2, we hypothesized that a measure to quantify BRCAness will identify the responders to PARP inhibitors that cause synthetic lethality in BRCA mutation tumors. Methods: The BRCAness score was established by using gene set variation analysis (GSVA) algorithm on 34 BRCA-mutation related genes. We investigated the clinical relevance of the score by performing silico analyses of 6245 breast cancer patients using multiple independent large cohorts in this study. Results: A score to quantify BRCAness was generated using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. The score was significantly associated with BRCA1 mutation, high overall mutation load and intratumoral heterogeneity as well as high HRD, DNA repair and MKI67 expression regardless of mutation in BRCA gene. High score tumor enriched not only DNA repair, but also five cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC targets v1 and v2, and MITOTIC signaling) in Hallmark collection (all false discovery rate < 0.10). Breast cancers with high score were significantly associated with higher infiltration of anti-cancerous immune cells and higher cytolytic activity. Not all breast cancer cell lines with BRCA-mutation showed high score and the other cells in human breast cancer tumor microenvironment were contributing to the score. We found that the BRCAness score was the highest in triple-negative among subtypes consistently in all cohorts (all p < 0.001). Finally, BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative (AUC = 0.815) and ER-positive/HER2-negative breast cancer (AUC = 0.715). Conclusions: We established a novel BRCAness score using mRNA expression of BRCA-mutation-related genes and found that it associates with DNA repair and response to PARP inhibitor regardless of BRCA mutation.
Cervical cancer geographical burden analyzer: An interactive, open-access tool for understanding geographical disease burden in patients with recurrent or metastatic cervical cancer.
Authors: Castellano Tara , Washington Christina , Moore Kathleen N. , Yildiz Yasin , Surinach Andy , Ting Jie , Chhatwal Jagpreet , Ayer Turgay
Published: June 2022

5523

Background: Examining geographic distributions of high and low proportions of recurrent or metastatic cervical cancer (r/mCC) can identify regions with high need of intervention and advance our understanding of r/mCC community-specific risk factors. Previous studies of epidemiologic or geographic clusters in late-stage cervical cancer were conducted prior to the availability of modern treatments for r/mCC. Due to the rapidly evolving treatment landscape for r/mCC use of commercial claims is an important way to follow dynamic practice changes. Our study objective was to understand recent geographical disparities among r/mCC patients in the US. Methods: We developed a web-based tool, Cervical Cancer Geographical Disease Burden Analyzer, that allows users to quantify r/mCC disease burden across metropolitan statistical areas (MSA) over multiple years. The inputs to the web-based tool were extracted through a retrospective analysis of the 2015-2020 MarketScan commercial claims database using a previously validated methodology. We then calculated the r/mCC rate as the ratio of r/mCC cases over cervical cancer (CC) cases for each of the >400 MSA considered. The calculated MSA-specific r/mCC rate was visualized in an interactive US map,. The online interactive tool allowed the users to filter the results by year, age group, and minimum number of diagnoses at the MSA level. Results: Our findings showed that there is large variation with respect to r/mCC disease burden across MSA in the US, with a range of 0-45%. The top five MSA with the highest r/mCC rates from 2018-2020 are presented in the table. In particular, r/mCC rates in Sacremento-Roseville-Arden-Arcade (SRAA), CA and Boston-Cambridge-Newton (BCN), MA were on an increasing trajectory (33% in 2018 to 50% in 2020 in SRAA, CA; and from 41% in 2018 to 50% in 2020 in BCN, MA). On the other hand, while disease burden remained high, we observed decreasing r/mCC rates in Grand Rapids, MI (55% in 2018 and 31% in 2020, resulting in an average r/mCC rate of 42%). Finally, in Cape Coral-Fort Myers, FL and Baltimore-Columbia-Towson, MD the r/mCC rates have fluctuated across time but were consistently >30%. Conclusions: Our web-based online interactive tool can help with identifying areas with high need of intervention, and inform how access, prevention and new or emerging therapies may potentially change the distribution of r/mCC disease burden. To better understand underlying drivers of geographic disparities observed, further efforts should be targeted towards identifying local-level factors. [Table: see text]
Efficacy and safety of the anti–PD-L1 monoclonal antibody socazolimab for recurrent or metastatic cervical cancer: Results from the phase I dose-escalation and expansion study.
Authors: An Jusheng , Guiling Li , Tang Jie , Li Benjamin Xiaoyi , Xiong Hui Hua , Qiu Hui , Luo Lin , Wang Li , Wang Danbo , Zhou Qi , Xu Qin , Song Hong Lin , Zhang Yun Yan , Zhang Hong Ping , Ng Rachel , Zhao Zewei , Dai Xiang Rong , Li Yu Jie , Sun Yuanjue , Wu Lingying
Published: June 2022

5526

Background: The study (NCT03676959) is an open-label, phase I study investigating the safety and efficacy of the recombinant, fully human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody socazolimab for recurrent or metastatic cervical cancer. Methods: Patients received socazolimab every 2 weeks until disease progression. The study was divided into a dose-escalation phase and a dose-expansion phase. Safety and tolerability were primary endpoints of the dose-escalation phase. Primary endpoints of the dose-expansion phase were safety and overall response rate (ORR) of the 5mg/kg dose. Efficacy was assessed by a third-party independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as the evaluation standard. Pharmacokinetics and pharmacodynamics were also studied. Results: One hundred four patients were enrolled. Twelve patients were included in the dose-escalation phase, with one complete and two partial responses in the 5mg/kg treatment group. Ninety-two patients (5mg/kg) were enrolled in the dose-expansion phase, with 54 patients (59.3%) expressing baseline PD-L1-positive tumors. ORR was 15.4% (95% CI, 8.7 to 24.5%). Median PFS was 4.44 months (95% CI, 2.37 to 5.75 months), and the median OS was 14.72 months (95% CI, 9.59 to NE months). ORRs for PD-L1-positive and PD-L1-negative patients were 16.7% and 17.9%, respectively. Treatment-related grade 3 to 4 adverse events occurred in 7.7% of patients. No treatment-related deaths had occurred. Conclusions: Our study demonstrates that socazolimab has remarkable safety and efficacy for the treatment of recurrent or metastatic cervical cancer and exhibits a safety profile similar to other anti–PD-1/PD-L1 monoclonal antibodies. Clinical trial information: NCT03676959. [Table: see text]
SPECT-defined, active bone marrow–sparing, volumetric-modulated arc therapy reduces the incidence of acute hematologic toxicity in patients with locally advanced cervical cancer who receive chemoradiotherapy.
Authors: Wang Shan Bing , Liu JiaPei , Jia Yuming , Lei Kaijian
Published: June 2022

5527

Background: Acute haematologic toxicity is the most common side effect of chemoradiotherapy in patients with locally advanced cervical cancer.We are aim to test the efficacy of defined active bone marrow sparing volumetric-modulated arc therapy reduces grade 3 or higher (grade 3+) acute haematologic toxicity for patients with locally advanced cervical cancer treated with chemoradiotherapy. Methods: This was a prospective, single-center, open label, randomized clinical trial that enrolled locally advanced cervical cancer.Patients were randomized to 99mTc sulfur colloid SPECT-defined active bone marrow sparing volumetric-modulated arc therapy group (ABMS group) or control group.The control group received weekly cisplatin concurrently with volumetric-modulated arc therapy(VMAT),followed by high-dose-rate intracavitary brachytherapy. The active bone marrow sparing volumetric-modulated arc therapy group additionally received 99mTc sulfur colloid SPECT-defined active bone marrow dose constrain. The primary endpoint was the incidence of grade 3 or higher (grade 3+) acute haematologic toxicity. Secondary objectives included acute gastrointestinal toxicity, planning Target Volume (PTV) coverage and dosimetric parameters of organs at risk(OARs). Results: A total of 148 patients with Federation of Gynaecology and Obstetrics(FIGO) stage IB-IIIB fromJanuary 2017 to April 2019 were randomized，and 146 were treated(74 in ABMS group and 74 in control group). The median follow-up was 20.0 months.The incidence of grade 3 or higher (grade 3+) acute haematologic toxicity in the ABMS group was 29.7%,significantly lower than the 48.6% incidence in the control group(p = 0.03).The incidence of grade 3+ neutropenia (ABMS group：20.3%,control group:36.5%;p = 0.04), Grade 3+ leukopenia (ABMS group：25.7%,control group:44.6%;p = 0.02) and Grade 3+ lymphopenia (ABMS group：4.1%,control group:14.9%;p = 0.04) were significantly differences between the two group.The were no differences in Grade 3+ anemia (ABMS group：1.4%,control group:5.5%;p = 0.37) and Grade 3+ acute gastrointestinal toxicity(ABMS group：1.4%,control group:1.4%;p = 1.00) between the two group.The number of patients completing five cycles of cisplatin in the ABMS group was 88.5%,,significantly higher than the 75% in the control group(p = 0.02).There were no differences in PTV coverage and dosimetric parameters of OARs between the two group. Conclusions: SPECT-defined active bone marrow sparing VMAT signifificantly reduced grade 3+ acute haematologic toxicity,and improved chemotherapy delivery compared with control group. Clinical trial information: ChiCTR-IOR-16010214.
Overall survival results from a phase II trial of anlotinib plus sintilimab in patients with recurrent advanced cervical cancer.
Authors: Xu Qin , Chen Chuan-ben , Sun Yang , Huang Zhangzhou , Lin Yibin , Liu Jing , Li Li , Li Zirong , Pan Junping , Chen Ying
Published: June 2022

5536

Background: The anlotinib (a novel multi-target TKI, inhibiting tumor angiogenesis and proliferative signaling) plus sintilimab (an antibody against PD-1) in patients with advanced cervical cancer trial was a multicenter, single-arm, phase II study (ChiCTR1900023015) that showed promising activity. The results of this trial have been previously reported and here we present updated survival data after a median follow-up of 13.0 months. Methods: Pts who have received at least once platinum-based chemotherapy, recurrent advanced cervical cancer, PD-L1 for CPS≥1, ECOG 0-1 were considered eligible for enrollment. Anlotinib was taken orally (10mg, qd, d1-14, 21 days per cycle), and sintilimab was administered intravenously (200mg, q3w, d1). The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS), safety and biomarkers. Results: Between December 2019 and December 2020, 42 patients with a median age of 53 years (range 36 to 67 years) were enrolled and received study treatment (ITT population and safety population). The data cutoff date was February 10, 2022. The patients were followed up for median duration of 13.0 months (range 0.03 to 24.8 months). In the ITT population, 2 (4.8%) patients achieved CR and 21 (50%) attained PR, the confirmed ORR was 54.8% (95% CI 38.7% to 70.2%). Fourteen (33.3%) patients had SD and the DCR was 88.1% (95% CI 74.4% to 96.0%). In the efficacy-evaluable patients (n = 39), the ORR was 59% (95% CI 42.1% to 74.4%) and the DCR was 94.9% (95% CI 82.7% to 99.4%). The median PFS was 9.46 months (95% CI 8.2 to 11.9) and the 6-month PFS rate was 73.4% (95% CI 60.6% to 89.0%). OS events occurred in 18 patients (42.9%). The median OS was 17.4 months (95% CI 12.4 to not reached). The 12-month OS rate and 24-month OS were 71.8% (95% CI 59.0% to 87.4%) and 49.1% (95% CI 34.5% to 69.9%), respectively. Conclusions: Anlotinib plus sintilimab showed a long-term survival benefit for patients with recurrent advanced cervical cancer. Additional investigations in larger randomized controlled trials are warranted in the future. Clinical trial information: ChiCTR1900023015.
Phase Ib INEOV neoadjuvant trial of durvalumab +/- tremelimumab with platinum chemotherapy for patients (pts) with unresectable ovarian cancer (OC): Final complete resection and pathological response rates.
Authors: Leary Alexandra , De La Motte Rouge Thibault , Lortholary Alain , Asselain Bernard , Alexandre Jerome , Floquet Anne , Savoye Aude Marie , Delanoy Nicolas , Gavoille Céline , You Benoit , D'hondt Veronique , Grenier Julien , Genestie Catherine , Chardin Laure , Pujade-Lauraine Eric ,   GINECO (Groupe d’Investigateurs Nationaux pour l’Etude des Cancers de l’Ovaire et du sein)
Published: June 2022

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Background: We have shown that neoadjuvant carboplatin and paclitaxel (NACP) increased tumor infiltrating lymphocytes and PDL1 expression in OC pts. INEOV evaluated NACP with durvalumab (D) +/- tremelimumab (T) in pts with unresectable OC. We previously reported that NACP with D+/-T was feasible and safe but the addition of T did not improve interval debulking surgery (IDS) rates after 3 cycles (C3) (ESMO 2021). Here we provide an update with longer follow up including data on delayed IDS performed after 6 cycles of neoadjuvant treatment. Key secondary endpoints include complete resection (CC0) and complete pathological response rates. Methods: Pts with stage IIIC/IV OC were randomized to NACP + D (1125mg) alone (arm A) or with T (75mg once at C2) (arm B). Interval debulking surgery (IDS) was planned after C3, or delayed after C6. Pts in arm A not operable after C3 crossed over to arm B, pts in arm B crossed over to standard of care (SOC). Pts were assessed for delayed IDS after C6. Complete pathological response (pCR) was defined as no residual tumor cells found on any surgical specimens, or no residual tumor cells on any samples outside the ovary at IDS. Results: Sixty four (N = 64) of 66 pts (IIIC/IV: 70%/30%) randomized were evaluable. After C3, 66% (21/32) of pts in arm A and 59% (19/32) in arm B had IDS. The 11 pts in arm A not candidate for IDS after C3 crossed over to arm B until C6 and 5/11 benefited from delayed IDS. The 13 pts in arm B inoperable at C3 went on to receive SOC (NACP +/- bevacizumab), and 5/13 became eligible for delayed IDS after C6. Overall, IDS was performed in 50 of 64 evaluable pts, and most (45/50) achieved macroscopically complete resection (CC0), so that the overall CC0 rate was 70% (45/64), with no significant difference between arms (CC0 = 75% vs 65% in arm A vs B). Among the 50 pts who had IDS, complete pathological responses were observed in 18% of pts. Conclusions: Taking into account the whole treatment strategy including delayed IDS after 6 cycles of neoadjuvant treatment, we have shown that neoadjuvant CP with D+/- T results in encouraging CC0 (70%) and pCR (18%) rates. However there was no apparent benefit to the addition of T to D. Studies are ongoing to describe the immune features predictive of pCR as well as the impact of treatment on the immune microenvironment. Clinical trial information: NCT03249142.
Identifying disparities in gynecologic cancer: Results and analysis from a patient preference survey.
Authors: Chapman-Davis Eloise , Halla Kimberly J. , Westin Shannon Neville , Salani Ritu , Constanzo Jerfiz D. , Quill Timothy A. , Burn Kathryn , Secord Angeles Alvarez
Published: June 2022

5561

Background: Health disparities exist in gynecologic cancers, with data revealing lower survival among certain racial/ethnic groups. Studies suggest underrepresented patients of color with gynecologic cancers may not receive guideline-concordant care to adequately manage their disease, including molecular testing. We conducted a patient preferences survey evaluating treatment choices and provider interactions influencing adherence to guideline-based care. Methods: From July 7 to August 18, 2021, a survey was sent to women with gynecologic cancers who participate in the SMART Patients advocacy group. Survey questions covered topics of preparedness to discuss care with provider, biomarker testing specific to gynecologic tumor type, patients’ considerations informing treatment choices, and confidence to work with providers to improve their clinical and survival outcomes. Information regarding cancer diagnosis, stage, race, ethnicity, treatment, and genetic testing was obtained. Survey responses between non-Hispanic White patients (W) versus non-White (NW) underrepresented patients of color were compared and analyzed using descriptive statistics. Results: A total of 89 women with gynecologic cancers (67% ovarian, fallopian tube, and peritoneal; 21% endometrial; 9% vulvar or vaginal; and 2% cervical) participated in the patient survey. Amongst responders, 55% had localized disease while 36% indicated they had metastatic disease, and 9% did not know. Overall, 86.5% were W and 13.5% were NW (Asian, Black/African American, Native American or Pacific Islander, Hispanic, or mixed race). A higher proportion of NW compared to W patients said they were not at all prepared to discuss cost of treatment (18.2% vs 9.5%), treatment options (12.5% vs 4.5%), and side effects of treatment (20% vs 0%) with their provider; 31% of W patients discussed genetic testing and received resources from their provider compared with only 16.7% of NW patients, and a higher proportion of NW compared to W patients (37.5% vs 28.1%) indicated they were not confident in their ability to work with providers to improve their cancer treatment outcome. Conclusions: While a limitation of this study was low participation from diverse populations, the findings indicate that underrepresented NW patients felt less prepared to discuss treatment-related issues compared to W patients. Moreover, a large proportion of all patients with OC were not informed and/or aware about genetic testing, and approximately a third of participants were not confident in their ability to interact with provider to improve their outcomes. The results highlight opportunities to enhance health care provider education and community outreach to reduce gaps in care delivery.