bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]