bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in the use of neoadjuvant chemotherapy for low-grade serous ovarian cancer in the United States.
Authors: Silberman Jason , Bercow Alexandra , Gockley Allison Ann , Eisenhauer Eric L , Sisodia Rachel , Randall Thomas Christopher , Melamed Alexander , Bregar Amy
Published: June 2023

5581

Background: Following the publication of randomized trials demonstrating its noninferiority, the use of neoadjuvant chemotherapy (NACT) for the treatment of advanced stage epithelial ovarian cancer has increased substantially in the United States. However, low-grade serous ovarian cancers (LGSOC) respond poorly to chemotherapy compared with high-grade serous carcinoma. For LGSOC, clinical guidelines favor surgical resection prior to adjuvant therapy. This study seeks to describe patterns and temporal trends in the use of NACT for LGSOC. Methods: This cohort study identified women treated for stage III or IV LGSOC in a Commission on Cancer accredited cancer program between January 1, 2004, to December 31, 2020. We fit Poisson regression models to evaluate temporal trends in the use of NACT and cytoreductive outcomes, and to identify factors associated with receipt of NACT. We considered age, race/ethnicity, Charlson Comorbidity Index, year of diagnosis, insurance status, income, facility type, census region, and stage as potentially associated with NACT. Due to the high rate of missingness in data describing cytoreductive outcomes after surgery, we undertook both multiply imputed and complete case analyses. Results: A total of 3,343 patients received treatment for LGSOC during the study period. The mean age at diagnosis was 54.8 year (SD 15.5) and most patients (82%) were white. The most commonly observed upfront treatment strategies were cytoreductive surgery followed by adjuvant chemotherapy (63.7%) and surgery without chemotherapy (19.2%). Treatment with NACT followed by interval cytoreductive surgery (13.0%) or chemotherapy alone (4.1%) were less common. The proportion of patients who received NACT increased from 9.5% in 2004 to 25.9% in 2020, corresponding to a statistically significant annual percent change (APC) of 7.2% (95% CI 5.6-8.9). Increasing decade of age (risk ratio [RR] 1.15; 95% CI 1.09-1.23), increasing calendar year of diagnosis (RR 1.07; 95% CI 1.05-1.08) and stage IV disease (RR 2.66; 95% CI 2.3-3.07) were associated with a higher probability of receiving NACT. Other variables were not associated with receipt of NACT. Among patients who underwent cytoreductive surgery, the proportion who achieved no gross residual disease remained stable over the course of the study period in both complete case (APC 0.5%; 95% CI -1.8 to 0.9) and multiply imputed (APC -0.1%; 95% CI -1.6 to 1.3) analyses. Conclusions: The use of NACT for patients with LGSOC increased substantially from 2004 to 2020. Despite increased utilization of NACT, the rate of complete cytoreduction has not improved over the study period, possibly calling into question the effectiveness of NACT in reducing tumor burden in this setting.
Ovarian cancer and bevacizumab: Real-world use across western countries and effect on survival in high-risk subgroups.
Authors: Lindemann Kristina , Abreu Miguel , de Lurdes Batarda Maria , Boll Dorry , Ekmann-Gade Anne Weng , Hansen Jesper , Haug Ala Jabri , HÃ¸gdall Claus , Korach Jacob , Van Nieuwenhuysen Els , Ottevanger P. B. , Polterauer Stephan , Henrichsen Schnack Tine , Agesen Trude , Waldemarson Sofia , Andersen Klaus Kaae , Marth Christian
Published: June 2023

5587

Background: Bevacizumab (bev) may be part of first-line treatment for patients with “high-risk” epithelial ovarian cancer (OC) (GOG-0218 and ICON7 trials). The prevalence of high-risk patient subgroups, including bev use and its effect on survival in a real-world setting is not well studied. Methods: The observational multi-country cohort study RESPONSE collected retrospectively medical record data on women with newly diagnosed advanced high-grade serous or endometrioid OC (DOI: 10.1002/cncr.34350). We analysed patients defined as ‘high-risk’ according to ICON7 definition as either 1) stage IV disease, 2) inoperable stage III disease or 3) sub-optimally debulked (>1 cm residual disease) stage III disease. Unadjusted Cox proportional hazards regression analysis was performed to estimate the association of bev with the risk of death. Follow up time was calculated from time between response assessment at the end of primary chemotherapy and death or 20 months follow-up, whichever occurred first. Results: Of 954 patients in total, we identified 386 high-risk patients (40%) treated with platinum-based chemotherapy. Of these, 132 (34%) received bev maintenance treatment. Baseline characteristics did not differ between patients receiving bev or no bev. Bev use was associated with a statistically significant reduction in risk of death with a HR of 0.49 (95%Ci: 0.18-0.78, p=0.002) in the total group of high-risk patients. The effect on survival was most evident among inoperable stage III/IV patients (n=151) with a 63% reduction in risk of death (HR 0.37; 95% CI (0.18-0.78, p=0.009). Risk estimates for additional subgroups are given in the table. Conclusions: Forty percent of this real-world population are considered high-risk according to ICON-7 and a majority of these patients did not receive bev during first-line treatment. In line with ICON 7, this analysis supports the beneficial effect of bev on overall survival in this high-risk population. Patients who do not receive surgery are underrepresented in clinical trials and this real-world study confirms the strong benefit of bev particularly in this subgroup. Any real-world study may be limited by the potential presence of selection bias of patients to receive bevacizumab or not. [Table: see text]
Predictors of long-term progression-free survival (PFS) in niraparib-treated patients (pts) from the PRIMA/ENGOT-OV26/GOG-3012 study.
Authors: Graybill Whitney , Pardo Beatriz , O'Malley David M. , Vergote Ignace , Monk Bradley J. , Auranen Annika , Copeland Larry J. , Sabbitini Roberto , Herzog Thomas J , Follana Philippe , Pothuri Bhavana , Braicu Elena Ioana , McCormick Colleen , Yubero-Esteban Alfonso , Moore Richard G. , Vuylsteke Peter , Raashouu-Jensen Nicoline , York Whitney , Hartman John , Gonzalez Martin Antonio
Published: June 2023

5589

Background: Niraparib was approved as maintenance therapy for pts with advanced ovarian cancer (OC) after complete or partial response (CR/PR) to first-line (1L) platinum-based chemotherapy (CT) based on results from the PRIMA study. In this post hoc analysis, we identified factors associated with long-term PFS. Methods: PRIMA is a phase 3, randomized study of pts with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer at high risk for relapse with CR/PR after 1L platinum-based CT. Pts were randomized 2:1 to niraparib 200 or 300 mg or placebo QD, and stratified by best response to 1L CT (CR/PR), neoadjuvant CT (yes/no), and homologous recombination deficiency (HRD) status (deficient [HRd]/proficient or not determined [HRp/nd]). Investigator-assessed PFS was dichotomized in niraparib-treated pts with progressive disease (PD)/censoring <2 years vs PD/censoring ≥2 years after randomization (data cut, Nov 17, 2021). Logistic regression modeling using backward elimination (significance level=0.15) was used to identify baseline covariates associated with long-term PFS. Results: Of 487 niraparib-treated pts, 152 (31%) had PD/censoring ≥2 years after randomization. Odds ratios (OR) for PFS ≥2 years by baseline subgroup are shown (Table). The logistic regression model showed that BRCA mutation and HRD status, International Federation of Gynecology and Obstetrics (FIGO) stage, fallopian tube as the site of the primary tumor, and absence of baseline nontarget lesions were associated with longer PFS. Eastern Cooperative Oncology Group (ECOG) performance score, body mass index, age, time from CT to randomization, number of target lesions, best response after CT, number of CT cycles, type of debulking surgery, and residual disease were not associated with PFS ≥2 years. Safety has been reported previously ( Ann Oncol. 2022;33[suppl 7]:S789). Conclusions: Results suggest that long-term PFS in pts treated with niraparib may be associated with BRCA/HRd biomarker status, FIGO stage, primary tumor site, and number of baseline non-target lesions. These data are hypothesis generating. Clinical trial information: NCT02655016 . [Table: see text]
Utility of Ki67 in guiding adjuvant abemaciclib therapy for patients with hormone receptor (HR)-positive, early breast cancer (EBC).
Authors: Patel Rima , Bilani Nadeem , Tiersten Amy , Sparano Joseph A.
Published: June 2023

559

Background: The monarchE trial found that the addition of adjuvant abemaciclib to endocrine therapy in pts with lymph node (LN)+, HR+ EBC improved invasive disease-free survival in two pt cohorts: (1) ≥ 4 +LNs or 1-3 +LNs and Grade 3 disease or tumor ≥ 5 centimeters and (2) 1-3 +LNs and Ki67 ≥ 20%. The FDA approved adjuvant abemaciclib only in pts with HR+, HER2-negative, LN+ EBC with Ki67 ≥ 20%. The role of Ki67 as a predictive biomarker in this setting is unclear. ASCO guidelines recommend offering abemaciclib to pts who meet eligibility for either cohort and not restricting inclusion by Ki67. The objectives of this study were to (1) determine the association between Ki67 and the 21-gene recurrence score (RS), an established prognostic and predictive biomarker, using Ki67 cutoff ≥ 20% and (2) compare eligibility for adjuvant abemaciclib by FDA versus ASCO criteria. Methods: Women with HR+, HER2-negative EBC with 1-3 +LNs, diagnosed between 2018 and 2019, and who had available information on Ki67 and RS in the National Cancer Database were identified. Pts were categorized into Ki67 low ( < 20%) or high ( ≥ 20%) based on cutoff used in the monarchE and stratified by RS of low-intermediate (0-25) or high (26-100). Stratified agreement between Ki67 and RS were assessed using the proportion of agreement and Kappa statistic. McNemar’s test was used to compare proportion of pts eligible for abemaciclib by FDA versus ASCO criteria. Results: 5,137 eligible women were included. 61.1% (n = 3,140) had Ki67 < 20% and 38.9% (n = 1,997) Ki67 ≥ 20%. There was fair agreement (Kappa 0.21-0.40) between Ki67 and RS, which was statistically significant (Kappa = 0.25, p < 0.001). Overall, using the FDA criteria for abemaciclib, 38.9% (n = 1,997) of patients would be eligible while based on ASCO criteria, 43.5% (n = 2,235) could be offered adjuvant abemaciclib (p < 0.001). Among the 2,235 patients eligible for abemaciclib based on ASCO criteria, 57.0% (n = 1,273) were eligible due to Ki67 ≥ 20% alone, 10.6% (n = 238) due to Grade 3 alone, while 32.3% (n = 724) satisfied both Ki67 ≥ 20% and Grade 3 criteria. There were 3,431 patients who were post-menopausal with RS 0-25 and would be spared chemotherapy, yet 35.3% (n = 1,212) would be eligible for adjuvant abemaciclib based on FDA or ASCO criteria. Conclusions: There was only fair agreement between Ki67 and RS in patients with 1-3 +LNs based on Ki67 cutoff of 20%. Among patients with LN+ EBC, more patients would be offered abemaciclib using ASCO criteria compared to FDA criteria. Most were eligible for abemaciclib based on Ki67 alone, suggesting that Ki67 may provide additional information beyond tumor grade. In postmenopausal women with 1-3 +LNs, about 30% may be spared adjuvant chemotherapy based on the RS but still be sufficiently high risk to be considered for adjuvant abemaciclib.
The effect of megestrol acetate ± pterostilbene in endometrial cancer: A prospective, randomized, window-of-opportunity clinical trial.
Authors: Senguttuvan Rosemary , Frankel Paul Henry , Ruel Nora , Kebria Mehdi , Han Ernest Soyoung , Song Mihae , De Leon Maria , Invernizzi Marta , Eng Melissa , Tinsley Raechelle , Li Aimin , Schmolze Daniel , Chang Sue , Arias Stella Javier , Dellinger Thanh Hue
Published: June 2023

5597

Background: Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant found naturally at highest concentrations in blueberries. Its anti-tumor effects in preclinical studies of various solid tumors include carcinogenesis, inflammation, reactive oxygen species (ROS) formation, and antiproliferative effects. In endometrial cancer (EC), in vitro and in vivo studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) in combination with megestrol acetate (MA). No clinical trials testing the potential therapeutic benefit of pterostilbene in cancer have been completed. Methods: We performed a prospective, window-of-opportunity, randomized phase 2 clinical trial (NCT03671811) in patients with EC. Eligible patients had to be surgical candidates for treatment with hysterectomy and not have received prior therapy. The primary objective was to determine the effect of MA plus PT versus standard treatment of MA alone on tumor proliferation as measured by the Ki-67 index during the preoperative window. Patients were randomized 1:1 to one of two arms: MA+PT PO BID versus MA PO BID, for 3 weeks. The Ki-67 index was measured via hot-spot and H-score methodology in the preoperative tumor and hysterectomy specimen by two blinded pathologists whose measurements were averaged. The net change between pre- and post-operative specimens was calculated for each patient and expressed as a percentage. Toxicity was assessed using CTCAE grading. Results: A total of 44 patients with EC of all histologies were recruited to the study and included in the toxicity analysis. Median age was 61.9 years. Baseline demographics were comparable between both arms. Median treatment duration was 21 days (14-56), similar in both arms. One G3 hypertension was encountered in the MA arm; one G3 thromboembolic event in the MA+PT arm. Of 35 patients with sufficient treatment duration (>10 days) and available pre-and post-treatment specimens, 29 patients with endometrioid histology were evaluated for the ki67 analysis: 14 in the MA arm and 15 in the MA+PT arm. The MA+PT group demonstrated a -41.1% change in Ki-67 index by Hot Spot Score compared to -27.5% in the MA-only group (p=0.17). A similar trend was observed for the Ki-67 index by H Score methodology (-41.6% vs -26.7%, MA+PT vs MA, p=0.17). Conclusions: The combination of MA + PT in preoperative treatment of endometrial adenocarcinoma is well tolerated. The addition of Pterostilbene demonstrates a trend towards decreased Ki-67 index in endometrioid EC patients. Molecular studies are pending to delineate biomarkers associated with response. Clinical trial information: NCT03671811 .
Overall survival and subsequent therapy from a phase II study of sintilimab and anlotinib in patients with advanced or recurrent endometrial cancer.
Authors: Zeng Zhen , Wei Wei , Cui Lanyue , Jiang Zhihao , Li Jundong
Published: June 2023

5598

Background: Although the combination of immunotherapy and antiangiogenic agents has been proved a promising strategy in endometrial cancer, studies in Chinese patients are limited. In the earlier phase II study (NCT04157491), Chinese patients with recurrent or advanced endometrial cancer treated with sintilimab + anlotinib had an objective response rate of 73.9% (95% confidence interval [CI]: 51.6% to 89.8%). Here we further updated overall survival (OS) and subsequent therapy for this study. Methods: Patients with endometrial carcinoma progressed after platinum-based chemotherapy were enrolled. Sintilimab 200 mg was supplied intravenously on day one, whereas anlotinib 12 mg was administered orally on day 1 - 14 every three weeks. Results: Twenty-three patients were enrolled in the study. 47.8% of patients received ≥ 2 lines of prior chemotherapy; microsatellite instability-high/mismatch repair deficiency (MSI-H/dMMR) and microsatellite instability stable/mismatch repair proficient (MSS/pMMR) accounted for 39.1% and 60.9% of patients, respectively. We observed a median OS of 17.8 months (95% CI, 9.4 to 26.3 months). Patients with microsatellite instability-high (MSI-H) had superior OS than their counterparts (not available vs. 13.3 months; HR 0.15, 95% CI, 0.33-0.70; P = 0.006). All patients had dropped out of the cohort [56.5% progression disease (PD), 13.0% adverse events (AE)]. Notably, five patients with partial responses (PRs) obtained pathological or radiography complete responses (CRs) in the follow-up. Pathological CRs were confirmed in three patients with long-lasting PRs who underwent surgery, consistent with PET/CT scans. Two patients with PR continued to have tumor shrinkage following treatment cessation due to AE and achieved CR during follow-up. Three out of four patients with CR experienced recurrences. There were no new grade 3-4 AEs associated with therapy. Conclusions: In terms of OS, combining sintilimab and anlotinib had promising therapeutic effects. Pathological CR was observed in patients with long-lasting PR, thus exploratory surgery may be required in selected patients. Clinical trial information: NCT04157491 . [Table: see text]
Correlation of cardiovascular disease with racial disparities in endometrial cancer outcomes.
Authors: Depke Mitchell , Summey Rebekah , Hopp Elizabeth
Published: June 2023

5602

Background: Survival for Black women with endometrial cancer (EC) is shorter than that for non-Hispanic White (NHW) women, with a rate ratio for mortality of 1.98 per the American Cancer Society. Cardiovascular risk factors and disease are also more prevalent in Black women than NHW women. In women with breast cancer, Black patients received less optimal management of comorbidities and experienced increased cardiovascular disease (CVD)-related mortality as compared to White women. Similar to breast cancer, we hypothesize that CVD contributes to EC mortality disparities for Black women. Methods: In this retrospective cohort study, SEER and institutional data were utilized to investigate the contribution of CVD to outcomes for Black EC patients. The primary outcome was the contribution of cardiovascular mortality to the overall survival of Black patients. Secondary outcomes included identifying rates of new cardiovascular diagnoses, renal dysfunction, and adequacy of blood pressure control. The SEER cohort was defined using SEER*Stat 8.4.0.1. Uterine cancer patients were identified from the 2020 SEER Research Data. Survival by cause of death and proportion of deaths by cause of death were analyzed. Raw and adjusted hazard ratios for cardiovascular mortality were calculated. Next, institutional data was used to investigate survival, CVD diagnoses, renal dysfunction, and HTN in EC patients. Results: The SEER cohort contained 192,465 patients. Of these, 153,878 (80.8%) were White and 19,906 (10.3%) were Black. Black race was associated with decreased survival among patients who died of cardiovascular causes (HR 1.51, 95% CI 1.4 - 1.63, p < 2*10-16). When adjusted for age, stage, and histology, the hazard for decreased survival remained elevated for Black patients who died of cardiovascular causes (adjusted HR 1.65, 95% CI 1.52-1.77, p < 2*10-16). Our institutional cohort included 1491 patients, 1263 (84.7%) White and 151 (10.0%) Black. Black patients had a relative risk of death of 1.92 (95% CI 1.38 - 2.61) compared with White patients. Among patients with CVD, the hazard for death was 2.02 (95% CI 1.39 - 2.80). Black patients had significantly higher blood pressure, creatinine, and eGFR measurements. Conclusions: Racial outcome disparities in EC are multifactorial. CVD management will become increasingly important with the use of targeted therapies including lenvatinib and trastuzumab. Our study highlights an additional area of disparity and suggests possible interventions.
Laparoscopic versus open-surgery in FIGO stage II endometrioid endometrium cancers: Is there a prognostic effect?
Authors: Reimer Daniel Uwe , Bargujar Tanu Priya , Leitner Katharina , Steger Katharina , Bartl Thomas , Marth Christian , Zeimet Alain G
Published: June 2023

5605

Background: Based on two randomized trials (LACE and LAP2) minimal invasive surgery has turned into the surgical standard in early stage endometrial cancer including “high-risk” patients. However, these recommendations are predominately based on “low-risk” cancers, which are mainly represented in both trial collectives. We herein provide a retrospective study, which focuses on potential differences in clinical outcome in early stage endometrioid endometrial cancers with distinct risk constellations treated by laparoscopy or open surgery. Methods: 420 early stage endometrial cancers were retrospectively dichotomized according to the surgical approach and correlated to the recurrence rate and clinical outcome. In addition, subgroup analyses were performed according relevant clinical risk parameters, namely FIGO stage, grading and LVSI. Results: The analyzed collective consisted of 73.8% stage IA, 19.5% stage IB, and 6.7% stage II cases. Twenty-tree percent of patients exhibit G3 tumors and LVSI was detected in 12.4%. Minimal invasive surgery was performed in 54.5% of study patients. During a median follow-up of 5.0 years, recurrence or death were observed in 8.3% and 6.7%, respectively. Recurrences were predominately located in the vaginal cuff (n = 21; 60.0%), to a minor extent in loco-regional lymph nodes (n = 11; 31.4%), and in three patients (8.6%) in both sides. No distant metastases were detected at first recurrence. Also under consideration of the mentioned clinicopathologic parameters, the surgical approach in FIGO stage I did not influence the recurrence rate and patients’ survival. However, in a subgroup analysis of stage II disease, the laparoscopic approach was clearly associated with a significant higher recurrence rate (85.7% vs. 14.3%; p = 0.013). All of the recurrences were located in the vaginal cuff, and in one case, additional relapse was found in loco-regional lymph nodes. Moreover, laparoscopic surgery in stage II disease was associated with impaired progression-free and overall survival (HR 8.86 (1.008 – 20.85) and HR 6.36 (1.102 – 28.61), respectively). Conclusions: We herein demonstrate that a minimal invasive surgical approach in stage II endometrial cancer is associated with higher recurrence rates and impaired clinical outcome. These data could be interpreted to be in line with the results of the LACC trial in cervical cancer. Although, grounded on a retrospective analysis, these hypothesis-generating results warrants a confirmatory trial, which is ongoing in a much larger collective of stage II endometrial cancer patients.
Impact of surgical weight loss treatments on care burden among obese endometrial cancer survivors.
Authors: Noyes Katia , Myneni Ajay A , Boccardo Joseph , Zsiros Emese , Hoffman Aaron B
Published: June 2023

5607

Background: Among obesity-related cancers globally, 40% of disability adjusted life years lost are attributed to endometrial cancer (EC). EC patients are more likely to die of obesity-related complications rather than the cancer itself. Metabolic and bariatric surgery (MBS) is an effective weight loss treatment that has been shown to reduce prevalence and severity of many obesity-related chronic conditions. However, there is limited evidence on MBS on EC survivors. We examined the burden of patient healthcare utilization among EC survivors who did and did not undergo MBS. Methods: We utilized the SEER-Medicare database to identify 31,437 patients diagnosed with endometrial cancer between 2015 and 2017. We selected 9,229 (29.4%) patients with documented obesity (ICD codes) among whom 75 (0.8%) patients underwent MBS after completing EC treatment (2017-2019). EC survivors with and without a history of MBS were matched on age at EC diagnosis. We examined annualized Medicare inpatient and provider claims payments among EC-MBS (starting 3 months after the surgery, n=66) and EC-no MBS patients (2017-2019) and used Wilcoxon Rank-Sum tests to examine differences in payments in a 1:5 matched sample. Results: EC-MBS patients were younger (59.9 years) at the time of cancer diagnosis compared to EC-no MBS patients (68.2 years, p<0.01). In an age-matched sample, annualized median inpatient and provider claim payments among EC-MBS patients ($1,824) were lower than that of EC-no MBS patients ($2,920, p<0.01). Conclusions: Surgical weight loss achieves rapid and effective weight loss and has the potential to lower healthcare utilization among EC survivors but less than 1% of eligible patients receive the surgery. Further research is needed to better understand patient, provider, and access barriers to surgical weigh loss in patients with obesity-related cancers. [Table: see text]
A multicenter, single-arm, phase 2 study of surufatinib plus toripalimab for patients with advanced endometrial cancer.
Authors: Yuan Guangwen , Li Zhiping , Ye Feng , Zhang Bingzhong , Shen Lin , Zhang Yan-qiao , Yu Xianjun , Cheng Ying , Liu Baorui , Wang Jianliu , Chen Xiaojun , Zhou Jinghong , Shi Haiyan , Tan Panfeng , Fan Songhua , Shi Michael , Su Weiguo , Wu Lingying
Published: June 2023

5609

Background: Several immunotherapy monotherapies, or combined with antiangiogenic inhibitors, have shown antitumor efficacy in endometrial cancer (EMC) and been approved by FDA. However, therapeutic options for EMC after failure of first-line treatment remain scarce in China. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate the efficacy and safety of the combination of surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) with toripalimab (an anti-PD-1 antibody) for Chinese patients (pts) with EMC after failure of one or more prior lines of systemic treatment. Methods: Pts with EMC who progressed or were intolerable after at least one prior line of systemic antitumor therapy were eligible and enrolled. They received 21-day cycles of surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From August 2020 to March 2022, 28 pts were enrolled and received the combination treatment (median duration: 4.6 months). Median age was 58 years (range: 50-71), and 22 (78.6%) pts were endometrioid adenocarcinoma at diagnosis. 9 (32.1%) pts had received ≥2 prior lines of therapy. As of 28 Dec 2022, the median follow-up duration was 16.8 months. Microsatellite status was available in 25 pts. 20 with mismatch repair-proficient (pMMR) and 5 with mismatch repair-deficient (dMMR) were determined. All 28 pts were evaluable with at least one post-baseline tumor assessment. Efficacy results were: confirmed ORR, 28.6% (8 partial response [PRs]); DCR, 82.1%; mDoR, 5.7 months; mPFS (95%CI), 5.4 months (2.7, 8.3); 12-month OS rate, 71.0%. Among pts with pMMR, the confirmed ORR was 25.0%; DCR was 85.0%; mDoR was 4.2 months; mPFS (95%CI) was 4.0 months (2.7, 8.3); 12-month OS rate was 75.4%. All pts experienced at least one treatment-emergent adverse event (TEAE), and 19 (67.9%) of them reported grade ≥3 TEAEs. The most common (≥5% pts) grade ≥3 TEAEs were hypertension (28.6%), aspartate aminotransferase increased (14.3%), alanine aminotransferase increased (10.7%), proteinuria (7.1%), Gamma-glutamyltransferase increased (7.1%) and malignant neoplasm progression (7.1%). No new safety signals were observed. Conclusions: Surufatinib plus toripalimab had a promising antitumor activity and a manageable safety profile in pts with EMC after failure of one or more prior lines of systemic therapy. Clinical trial information: NCT04169672 .
Prognosis of squamous cell carcinoma of the breast by biological subtypes and the efficacy of radiotherapy: The Japanese Breast Cancer Registry analysis.
Authors: Ogita Mami , Kubo Makoto , Kumamaru Hiraku
Published: June 2023

561

Background: Primary squamous cell carcinoma (SCC) of the breast is a rare disease, accounting for about 0.1% of all breast cancers. We aimed to determine the clinical features and prognosis of breast SCC, and the effect of radiotherapy by biological subtypes using the Japanese Breast Cancer Registry. Methods: We conducted a matched-pair analysis of 350,977 breast cancer patients with SCC or invasive ductal cancer (IDC) in the Japanese Breast Cancer Registry between 2004 and 2014. Inclusion criteria were female breast cancer patients who underwent surgery with stage I–III diseases, SCC or IDC, and age ≥ 18. Patients who received preoperative radiotherapy were excluded. We performed 1:1 SCC-IDC exact matching analysis by predominant subtypes in SCC: ER(-) and PgR(-)/HER2(-) or ER(+) and/or PgR(+)/HER2(-). Overall survival (OS), breast cancer-specific survival (BCSS), recurrence-free survival (RFS), and first locoregional or distant metastasis recurrence incidence were compared between IDC and SCC by Kaplan-Meier methods and log-rank test. In-field area recurrence was compared between those who received radiotherapy and those who did not. Results: We included 452 SCC and 182,707 IDC patients for the analysis. SCC patients were more likely to present with advanced stage disease compared to those with IDC. Among SCC patients, 59% was ER(-)/PgR(-)/HER2(-), 19% was ER(+)/PgR(+)/HER2(-), 8% was ER(-)/PgR(-)/HER2(+), 2% was ER(+)/PgR(+)/HER2(+), and 12% was data missing. Ten-year OS, BCS, and RFS rates were 70%, 80%, and 66% in SCC, and 88%, 93%, and 81% in IDC, respectively, and SCC carried a significantly worse prognosis than IDC (all P < 0.001). For exact-matched analysis, 10-year BCS of ER(-)/PgR(-)/HER2(-) SCC patients was significantly worse than IDC (P = 0.02), whereas there were no significant differences between SCC and IDC of ER(+)/PgR(+)/HER2(-) patients in OS, BCS, and RFS. Among patients who received radiotherapy, no difference was found in in-field area recurrence between SCC and IDC in either ER(-)/PgR(-)/HER2(-) or ER(+)/PgR(+)/HER2(-) subtype. Conclusions: SCC of the breast was often diagnosed in an advanced stage and had a worse prognosis than IDC. More than half of them were triple-negative subtype. In the triple-negative subtype, SCC was an independent poor prognostic factor. No significant differences in in-field area recurrence after radiotherapy between SCC and IDC suggested that the effect of radiotherapy on local control for SCC was similar to IDC.
Lipidomic signature from plasma to detect localised breast cancer.
Authors: Lamoury Gillian , Batarseh Amani M. , Kehelpannala Cheka , Pascovici Dana , Li Desmond , Heffernan Kerry
Published: June 2023

565

Background: An effective and accurate blood test to detect localised breast cancer may increase the screening detection rate and improve patient outcomes. We have previously reported a series of lipidomic studies and derived a lipid signature from plasma enriched extracellular vesicles (EVs) that effectively distinguished people with localised breast cancer from cancer-free controls. here we report on a significant refinement to the test methodology allowing the assessment of the lipid signature directly from plasma samples and its performance, with the aim of advancing the commercial viability of the test as we move towards clinical application. Methods: Lipids were extracted from enriched EVs from plasma samples donated by fasted people with localised breast cancer and control samples (n=793) and analysed by high resolution accurate mass liquid chromatography-mass spectrometry (LC-MS). Over 400 manually curated lipids were quantified. Following variable selection, a lipid signature capable of distinguishing breast cancer samples from controls was derived. The lipid signature was modelled on each of the cohorts using leave-one-out internal cross-validation. Next, we analysed the lipids in cancer and control (n=256) plasma samples corresponding to patients from Cohorts 3 and 4 previously used for EV preparations, and applied the signature derived using EVs on plasma lipidomic data. Results: EV samples of people with breast cancer were distinguished from controls with an area under the curve (AUC) of 0.77-0.89 across 4 cohorts. When the lipid signature was assessed directly from plasma the test achieved a comparable AUC of 0.84. Assessing the markers directly from plasma samples would make the test more scalable, higher throughput and easier to perform. Conclusions: Our study demonstrated the high performance of a lipid biomarker signature derived from plasma enriched EVs for early detection of localised breast cancer. Our results suggest that that the lipidomic signature could potentially be assessed directly from plasma samples instead of EVs reducing the test complexity. Ongoing studies will optimise the plasma lipidomic signature and prospectively compare the test against mammographic and pathological diagnoses. [Table: see text]
Association of anthracyclines induced cardiotoxicity (AIC) in patients with early breast cancer (eBC) with germline BRCA1/2 (gBRCA1/2) mutation: BRCAN study.
Authors: Serrano Domingo Juan José , Cordero David , Menacho Miriam , del Rey Jose Manuel , Chamorro Jesús , Rosero Diana I. , Sotoca Pilar , del Campo Laura , Alonso Gonzalo , Saavedra Serrano Cristina , Fernández-Abad María , Gion Cortes Maria , Guerra Eva M. , Martinez-Jañez Noelia , Lopez-Miranda Elena , Vida Navas Elena Maria , Fuentes Mateos Raquel , GUILLEN PONCE CARMEN , Salazar Maria Teresa , Cortés Salgado Alfonso
Published: June 2023

567

Background: BRCA1/2 genes play a critical role in genome stability and DNA repair in human cells, including cardiomyocytes. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and cardiac mortality following anthracyclines (A) exposure. However, whether these preclinical findings translate to humans still remains unclear. We conducted the BRCAN study to assess the impact of gBRCA1/2 status on AIC in a cohort of patients with eBC. Methods: This is a single center retrospective/prospective study including patients diagnosed with HER2-negative eBC treated with A based chemotherapy in the neo/adjuvant setting, known gBRCA1/2 status, left ventricular ejection fraction (LVEF) ≥ 50% at baseline and no previous significant cardiovascular events. During follow-up, we performed myocardial dysfunction blood biomarkers (MDBB), cardiac ultrasound and quality of life questionnaires (QoL). Primary objective was to assess the absolute LVEF change from baseline in BRCA1/2 mutation carriers (gBRCA1/2mut) versus non-carriers (gBRCA1/2wt). Secondary objectives were comparing MDBB and QoL in these groups. Results: 137 patients with eBC were included in the study (103 gBRCA1/2wt and 34 gBRCA1/2mut). Patients’ characteristics were similar between both groups in terms of age, baseline LVEF, radiotherapy (RT) on left side, total A accumulative dose, time from A exposure, antihypertensive or hypolipidemic agents use and smoking habit. Compared to baseline, LVEF % reduction was -4.7 [-12.0, 0.0] versus -9.5 [-18.0, -5.0] in gBRCA1/2wt and gBRCA1/2mut, respectively (p=0.027). To correct for confounding, we fit a regression model for the variables smoking habit, antihypertensive and hypolipidemic agents use. On average, LVEF % reduction in gBRCA1/2mut group was -4.5 [CI 95% -8.6, -0.4, p=0.032] compared to gBRCA1/2wt. No differences between MDBB (protein C-reactive, hsTn, NT-ProBNP, D-Dimer, ST-2 or Galectine-3) and QoL (MLHFQ and EQ5-D index) were detected between groups. Conclusions: Our data suggest that gBRCA1/2mut patients could represent a high risk population for AIC. A baseline comprehensive cardiovascular risk assessment and a closer follow-up should be recommended in these patients. Further research is needed on order to identify early predictive biomarkers for AIC. [Table: see text]
ERBB2 mRNA expression to distinguish HER2-low/neg breast cancer prognosis.
Authors: Liu Yueping , Lv Hong , Shen Mengjia , Shui Ruohong , Ye Feng , Meng Yue , Jia Ying , Liu Chao , An Shun , Yuan Xiaoying , Li Xingmin , Yang Wentao , Bu Hong
Published: June 2023

569

Background: Antibody-drug conjugates such as Trastuzumab deruxtecan significantly improved progression-free and overall survival for the HER2 low expression (HER2-low) breast cancer (BC) patients, pushing the research field of HER2-low to a new climax. In fact, the traditional immunohistochemistry (IHC) to identify the HER2-low or HER2-negative expression (HER2-neg) has been challenged, and it cannot predict the prognosis of HER2-low/neg patients well. Methods: Three pathologists evaluated the HER2 expression status of the subjects via IHC. More than two pathologists judged HER2 0-2 and FISH negative samples were included in this trial. ERBB2 mRNA level of formalin-fixed, paraffin-embedded BC post-surgery specimens were detected by MammaTyper quantitative real-time polymerase chain reaction (qRT-PCR) kit. The consistency of HER2 immunohistochemistry (IHC) and MammaTyper results were analyzed by interclass correlation coefficients (ICC). Differences in disease-free survival (DFS) were assessed by Kaplan Meier analysis. Results: 793 cases were included. The ICC value between IHC and MammaTyper, assessed for HER2-neg vs HER2-low is 0.28. With a median follow up of 2.5 years, there were 36 events in the whole subjects. In the whole subjects, MammaTyper successfully showed that the prognosis of HER2-low was significantly better than HER2-neg (P < 0.001, HR = 3.497, 95%CI,1.807-6.77), but IHC could not distinguished them (P = 0.1071, HR = 1.776, 95%CI, 0.9194-3.43). Although the follow-up time is short, HER2-low subjects also showed better prognosis than HER2-neg in TNBC subjects distinguished by MammaTyper (P = 0.0271, HR = 2.912, 95%CI,1.129-7.511), not by IHC (P = 0.1032, HR = 2.213, 95%CI, 0.8512-5.756). However, in 291 cases of IHC and MammaTyper detection discordancy group, IHC results showed that the prognosis of HER2-low was worse, which was contrary to the MammaTyper results and the results of the above overall test results, suggesting that IHC could not verily reflect the amount of HER2 expression in some samples, and the prognosis of HER2-low population might be more related to the mRNA expression of HER2. Conclusions: Compared with IHC/FISH, MammaTyper qRT-PCR assay may actually reflect the prognosis of HER2-neg/low, which is expected to become a diagnostic beacon for HER2-low target drugs.
Outcomes in premenopausal patients with HR+/HER2- breast cancer and lymph node micro-metastasis based on the 21-gene recurrence score.
Authors: Bilani Nadeem , Patel Rima , Tiersten Amy
Published: June 2023

571

Background: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) <26 do not benefit from chemoendocrine therapy (‘CET’) compared to endocrine monotherapy (‘E’). The TAILORx and RxPONDER trials demonstrated this was consistent in node-negative and node-positive disease, respectively. In premenopausal patients, however, guidelines for those with low RS diverge between disease involving 0 (pN0) vs. 1-3 (pN1a-c) lymph nodes. Additionally, treatment decisions are less clear for patients with micro-metastasis (pN1mi), who comprised only about 10% of patients in RxPONDER. This study used the National Cancer Database (NCDB) to assess treatment patterns and survival outcomes in premenopausal patients with EBC and lymph node micro-metastasis. Methods: A cohort of patients aged <50, diagnosed between 2004-2019 with HR+/HER2- EBC and who underwent ODX testing, was recruited from the NCDB. (A) Firstly, we described demographic and clinical characteristics of a sub-cohort with micro-metastasis using univariate statistics. (B) We confirmed the prognostic value of ODX in this sub-cohort with multivariate Cox regression analysis of overall survival (OS). (C) We explored patterns of practice amongst the total cohort with ODX <26 with chi-squared testing for differences in CET use by nodal status. (D) To elucidate the predictive value of this assay, we performed Kaplan-Meier models comparing OS for those with RS <26 receiving E vs. CET, controlling granularly for nodal status: (i) pN1a-c, (ii) pN1mi, and (iii) pN0. Results: Of n=72,068 patients aged <50 with HR+/HER2- EBC and ODX data, 6.1% (n=4,402) had micro-metastasis. (A) The median age of this subgroup was 45 (IQR 41-47) years. Most tumors were grade II (n=2,472, 57.7%) with ductal histology (n=3,500, 80.3%). 73.4% of pN1mi cases had RS <26, while 26.6% had RS ≥26. (B) Multivariate Cox regression – adjusting for comorbidity, race and chemotherapy use – confirmed significance in this pN1mi cohort of RS ≥26 prognosticating poorer OS compared to RS 0-15 (HR 4.42, 95% CI 2.35-8.31, p<0.001). (C) 29.0% (n=1,033) of patients with pN1mi and ODX <26 underwent CET, greater than 15.2% (n=6,568) with pN0 and less than 47.3% (n=2,884) with pN1a-c staging (p<0.001). (D) A benefit in OS (p=0.017) was observed in cases with RS<26 and pN1a-c using CET (5-year OS: 99%) vs. E (5-year OS: 97.5%), but not in pN1mi (p=0.49) or pN0 (p=0.57) disease. Conclusions: The management of premenopausal patients with HR+/HER2- EBC, isolated micro-metastasis, and ODX <26 is unclear. Our large registry study found the addition of chemotherapy to endocrine therapy was associated with improved survival in cases with ODX<26 involving 1-3 lymph nodes, but not in node-negative or micro-metastatic disease. Prospective trials are needed to confirm these findings.
Somatic mutations in tumor-adjacent normal breast tissue in young women with high risk family history.
Authors: Rozenblit Mariya , Suwalska Aleksandra , Hofstatter Erin Wysong , Reisenbichler Emily , Harigopal Malini , Marczyk Michal , Pusztai Lajos
Published: June 2023

576

Background: It’s incompletely understood why some women without germline breast cancer predisposing mutations develop early onset breast cancer. Breast cancer in young women is often more aggressive, with high histologic grade, worse prognosis, and higher risk of recurrence. We hypothesize that these women have somatic mutations in the normal breast tissue that contribute to breast cancer tumorigenesis. Methods: Whole exome sequencing (WES) data was analyzed from normal tissue adjacent to breast tumor and compared to matched peripheral blood (n=28). All patients were <50yo, had high risk family history as per NCCN guidelines, and had negative Ambry Genetics panel testing. FFPE sections were reviewed by two pathologists to identify normal breast tissue furthest away from tumor. WES was performed on Illumina HS4000 using 100-base pair paired-end reads. Samples were mapped to the human reference genome (vGRCh38). PCR duplicates were marked (Picard), and indel regions were adjusted (GATK). High-quality germline variants (HaplotypeCaller), somatic mutations (Mutect), and indels (IndelGenotyper) were called. Low-quality variants were filtered out. The classification and number of mutations per gene per sample were extracted and analyzed. Results: Majority of patients were white (86%), median age 45, with invasive ductal carcinoma (86%), ER+/PR+/HER2- (100%). Median somatic variants per sample were 97 (range: 45-285), all single nucleotide variants, mostly missense mutations, C>T conversions were seen in 45% of mutations. This suggests cytidine deaminase (APOBEC) involvement. All samples had alterations in at least one of the top ten affected genes which include transcription factors in zinc finger family (listed below). Zinc finger proteins play a key role in tumorigenesis, cancer progression and metastasis in a variety of cancers. Upregulation of zinc finger proteins has been associated with worse prognosis in breast cancer. Conclusions: We describe novel somatic mutations in zinc finger proteins in normal breast tissue adjacent to tumor that may contribute to early onset breast cancer in patients with high risk family history. [Table: see text]
Extracellular vesicle-derived non-coding RNAs to predict outcome in patients with triple-negative breast cancer (TNBC) with residual disease (RD).
Authors: Stecklein Shane R , Koestler Devin , Yellapu Nanda K , Yoder Rachel , Kimler Bruce F. , Staley Joshua M. , Schmitt Zachary , Khan Qamar J. , O'Dea Anne , Nye Lauren Elizabeth , Elia Manana , Heldstab Jaimie , Home Trisha , Hyter Stephen , Isakova Kamilla , Pathak Harsh B , Godwin Andrew K. , Sharma Priyanka
Published: June 2023

578

Background: TNBC patients with RD after neoadjuvant systemic therapy (NAST) have high risk of recurrence. Biomarkers to risk-stratify patients with RD could individualize adjuvant therapy and inform adjuvant therapy trials. We aim to investigate the impact of circulating extracellular vesicle (EV)-derived non-coding RNAs (exo-ncRNAs) on outcomes in TNBC patients with RD. Methods: The study population included 79 TNBC patients with RD post-NAST and available end-of- treatment plasma samples enrolled in an IRB-approved multisite prospective registry. EVs and their associated exo-ncRNAs were isolated by membrane affinity spin columns (Qiagen exoRNeasy). Exo-ncRNA was subjected to next-generation sequencing (Qiagen QIAseq miRNA library kit). N=47 served as a discovery cohort and N=32 served as validation cohort. With inclusion of transcripts expressed in ≥ 80% of samples, there were 1,123 normalized reads/sample. Hazard ratios and C-statistics for event-free survival (EFS) were computed for each exo-ncRNA. We report exo-ncRNAs that were significantly associated with EFS in both the discovery and validation cohorts. Results: Patient and tumor characteristics were balanced in discovery and validation cohorts. Three exo-ncRNAs were associated with increased recurrence risk in both the discovery dataset ( miR-200a-3p, HR=1.39, 95%CI 1.01-1.89, P=0.04, C-stat=0.55; miR-203a-3p, HR=1.77, 95%CI 1.15-2.73, P=0.01, C-stat=0.59; and miR-7845-5p, HR=1.53, 95%CI 1.15-2.05, P=0.004, C-stat=0.62) and the validation dataset ( miR-200a-3p, HR=1.83, 95%CI 1.24-2.72, P=0.003, C-stat=0.76; miR-203a-3p, HR=1.78, 95%CI 1.10-2.87, P=0.02, C-stat=0.67; and miR-7845-5p, HR=2.06, 95%CI 1.06-4.01, P=0.03, C-stat=0.52). Using the miRNA Target Prediction Database (miRDB), we identified 1,088, 1,352, and 387 predicted targets for miR-200a-3p, miR-203a-3p, and miR-7845-5p, respectively. Amongst 2,827 prediction events there were 2,526 unique target mRNAs. 2,235 mRNAs were targets for one candidate miRNAs, 281 mRNAs were predicted targets for two candidate miRNAs, and 10 mRNAs were predicted as targets for all three candidate miRNAs. Conclusions: The expression of miR-200a-3p, miR-203a-3p, and miR-7845-5p in plasma-derived EVs in TNBC patients with RD after NAST is associated with increased risk of recurrence. We identified ten mRNAs that are predicted targets of all three of these miRNAs. If validated in additional cohorts these exo-ncRNAs could be used in a liquid-biopsy assay to identify high-risk patients with RD who could benefit from adjuvant treatment intensification. [Table: see text]